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  • 201.
    Kjellgren, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Ryan, Michelle
    Ohlendieck, Kay
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Sarco(endo)plasmic reticulum ca2+ATPases (SERCA1 and 2) in human extraocular muscles2003In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 44, no 12, p. 5057-5062Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the composition of the fibers in human extraocular muscles (EOMs) with respect to the sarco(endo)plasmic reticulum Ca(2+)ATPases (SERCA)-1 and -2 and to investigate possible correlations between SERCA and myosin heavy chain (MyHC) composition. METHODS: EOM samples were processed for immunocytochemistry with monoclonal antibodies specific against SERCA1 (fast isoform), SERCA2 (slow isoform), or different MyHCs. A total of 1571 fibers were analyzed. Microsomal EOM fractions were analyzed with SDS-PAGE and immunoblots. RESULTS: The fast fibers, containing MyHCIIa, accounted for 79% of the fibers in the orbital layer (OL) and 74% in the global layer (GL). More than 99% of these fibers contained SERCA1, and 86% of them coexpressed SERCA1 and -2. Almost all slow fibers stained with SERCA2; 54% of those in the GL and all in the OL coexpressed SERCA1 and -2. Fifteen percent of the fibers in the GL and less than 1% in the OL were MyHCeom(pos)/MyHCIIa(neg) fibers. All these contained SERCA1 and in the OL also stained strongly with anti-SERCA2. Biochemically SERCA2 was more abundant than SERCA1. CONCLUSIONS: The human EOMs had a very complex pattern of expression of the major protein regulating fiber relaxation rate. The coexistence of SERCA1 and -2, together with complex mixtures of MyHCs in most of the fibers provide the human EOMs with a unique molecular portfolio that allows a highly specific fine-tuning regimen of contraction and relaxation.

  • 202.
    Kjellgren, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Larsson, Lars
    Uppsala University.
    Fürst, Dieter
    University of Bonn.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Uncoordinated expression of myosin heavy chains and myosin-binding protein C isoforms in human extraocular muscles2006In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 47, no 10, p. 4188-4193Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To examine the distribution of myosin-binding protein C (MyBP-C) in human extraocular muscles (EOMs) and to correlate the myosin heavy chain (MyHC) and the MyBP-C composition of the fibers. METHODS: Samples from 17 EOMs, 3 levator palpebrae (LP), and 6 limb muscles were analyzed with SDS-PAGE and immunoblot or processed for immunocytochemistry with monoclonal antibodies (mAbs) against MyBP-C-fast, MyBP-C-slow, MyHCIIa, MyHCI, MyHCsto, MyHCalpha-cardiac, and MyHCemb. RESULTS: In the limb muscle samples, fast fibers were labeled with anti-MyBP-C-fast and anti-MyBP-C-slow, whereas the slow fibers were immunostained with anti-MyBP-C-slow only, in accordance with previous studies. In 11 EOM samples MyBP-C-fast was not detected, and weak staining with anti-MyBP-C-fast was seen only in a few fibers in the proximal part of 2 muscles. The mAb against MyBP-C-slow labeled all fibers, but fibers containing MyHCI were generally more strongly stained. In the levator palpebrae, immunostaining with anti-MyBP-C-fast was present in some fibers labeled with anti-MyHCIIa and/or anti-MyHCeom. MyBP-C-fast and -intermediate were not detected biochemically in the EOMs. CONCLUSIONS: The lack of MyBP-C-fast and intermediate is an additional feature of the human EOM allotype. The true EOMs have a unique myofibrillar protein isoform composition reflecting their special structural and functional properties. The levator palpebrae muscle phenotype is intermediate between that of the EOMs and the limb muscles.

  • 203.
    Kjellgren, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Andersen, Jesper
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Myosin heavy chain isoforms in human extraocular muscle2003In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 44, no 4, p. 1419-1425Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the myosin heavy chain (MyHC) composition of human extraocular (EOM) and levator palpebrae (LP) muscle fibers. METHODS: Adult human EOMs and LP were studied with SDS-PAGE, immunoblots, and immunocytochemistry, with antibodies against six MyHC isoforms. Myofibrillar adenosine triphosphatase (mATPase) and reduced nicotinamide adenine dinucleotide (NADH)-TR activity and fiber area were also determined. RESULTS: Most of the fibers in both layers stained strongly with anti-MyHCIIa. Approximately 14% of the fibers in the global layer and 16% in the orbital layer were labeled with anti-MyHCI. The remaining 24% of the fibers in the global layer and 3% in the orbital layer were not stained with either of these two antibodies, but were reactive to anti-MyHCeom (MyHCeom(pos)/MyHCIIa(neg) fibers). The fibers stained with anti-MyHCI had acid-stable mATPase activity, and the remainder of the fibers had alkaline-stable mATPase activity. Almost all the slow fibers stained with both anti-MyHCI and anti-MyHCslow tonic in both layers. Anti-MyHCalpha-cardiac stained approximately 26% of these slow fibers in the orbital layer and 7% in the global layer. Some slow fibers in both layers lacked staining with anti-MyHCslow tonic or with anti-MyHCalpha-cardiac. MyHCemb and/or MyHCeom were also present in some of the fibers of all the groups. The LP did not stain with anti-MyHCslow tonic. CONCLUSIONS: The present study revealed that the human EOMs have a very complex fiber type and MyHC composition and differ significantly from the EOMs of other species. The features of the LP were distinct from those of the four recti, the obliquus superior, and the limb muscles.

  • 204.
    Kjellgren, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Virtanen, Ismo
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Laminin isoforms in human extraocular muscles2004In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 45, no 12, p. 4233-4239Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To determine the laminin isoform composition of the basement membranes (BMs) in the human extraocular muscles (EOMs) and relate it to the fact that EOMs are spared in laminin alpha2-chain-deficient congenital muscular dystrophy. METHODS: Samples from adult human EOMs and limb muscle were processed for immunocytochemistry, with monoclonal antibodies against laminin chains (Ln) alpha1 to -5, beta1 and -2, and gamma1. Neuromuscular junctions (NMJs) were identified with acetylcholinesterase reaction. The capillary density was measured in sections stained with anti-Lnalpha5. RESULTS: The extrasynaptic BM of the EOM muscle fibers contained Lnalpha2, -beta1, -beta2, and -gamma1, and, in contrast to limb muscle, it also contained Lnalpha4 and -alpha5, to some extent. The distinct laminin composition of the EOMs was confirmed by the presence of Lutheran protein, an alpha5-chain-specific receptor not found in limb muscle. At the NMJs, there was increased expression of Lnalpha4 and expression of Lnalpha2, -alpha5, -beta1, -beta2, and -gamma1 was also maintained. The capillary density was very high (1050 +/- 190 capillaries/mm(2)) in the EOMs and significantly (P < 0.05) higher in the orbital (1170 +/- 180 capillaries/mm(2)) than in the global (930 +/- 110 capillaries/mm(2)) layer. CONCLUSIONS: The human EOMs showed important differences in laminin isoform composition and capillary density when compared with human limb muscle and muscles of other species. The presence of additional laminin isoforms other than laminin-2 in the BM of the extrasynaptic sarcolemma could partly explain the sparing of the EOMs in Lnalpha2-deficient congenital muscular dystrophy.

  • 205.
    Kolar, Mallappa K
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    The use of adipose derived stem cells in spinal cord and peripheral nerve repair2014Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Clinically, injuries affecting the spinal cord or peripheral nerves can leave those affected with severe disability and, at present, there are limited options for treatment. Peripheral nerve injury with a significant gap between the proximal and distal stumps is currently treated with autologous nerve grafting but this is limited by availability of donor nerve and has associated morbidities. In contrast, injuries to the spinal cord lead to an inhibitory environment caused by the glial cells and thereby, limit potential axonal regeneration. This thesis investigates the effects of human adipose derived stem cells (ASC) on regeneration after peripheral nerve and spinal cord injury in adult rats.

    Human ASC expressed various neurotrophic molecules and growth factor stimulation of the cells in vitro resulted in increased secretion of BDNF, GDNF, VEGF-A and angiopoietin-1 proteins. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In contrast to Schwann cells, ASC did not induce activation of astrocytes and supported neurite outgrowth from the adult rat sensory DRG neurons in culture.

    In a peripheral nerve injury model, ASC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, ASC enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the fibrin nerve conduits. The animals treated with stimulated ASC showed an enhanced axon regeneration and reduced caspase-3 expression in the DRG.

    After transplantation into the injured C3-C4 cervical spinal cord. ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowths of 5HT-positive raphaespinal axons into the trauma zone. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure and the density of the astroglial scar. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the reactivity of OX42-positive microglial cells was markedly reduced.

  • 206.
    Kolar, Mallappa K.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Department of Surgical and Perioperative Sciences, Faculty of Medicine.
    Transplantation of mesenchymal stem cells and injections of microRNA as therapeutics for nervous system repair2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Traumatic injuries to the spinal cord (SCI) and peripheral nerve (PNI) affect several thousand people worldwide every year. At present, there is no effective treatment for SCI and despite continuous improvements in microsurgical reconstructive techniques for PNI, many patients are still left with permanent, devastating neurological dysfunction. This thesis investigates the effects of mesenchymal stem cells (MSC) derived from adipose (ASC) and dental (DSC) tissue and chitosan/microRNA-124 polyplex particles on regeneration after spinal cord and peripheral nerve injury in adult rats. Dental stem cells were obtained from apical papilla, dental pulp, and periodontal ligament. ASC and DSC expressed MSC surface markers (CD73, CD90, CD105 and CD146) and various neurotrophic molecules including BDNF, GDNF, NGF, VEGF-A and angiopoietin-1. Growth factor stimulation of the stem cells resulted in increased secretion of these proteins. Both ASC and DSC supported in vitro neurite outgrowth and in contrast to Schwann cells, ASC did not induce activation of astrocytes. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In a peripheral nerve injury model, ASC and DSC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, both ASC and DSC promoted axonal regeneration in the conduit and reduced caspase-3 expression in the dorsal root ganglion (DRG). ASC also enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the implant. After transplantation into injured C3-C4 cervical spinal cord, ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure and the density of the astroglial scar. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the reactivity of OX42-positive microglial cells was markedly reduced. However, ASC did not enhance recovery of forelimb function. In order to reduce activation of microglia/macrophages and the secondary tissue damage after SCI, the role of microRNA-124 was investigated. In vitro transfection of chitosan/microRNA-124 polyplex particles into rat microglia resulted in the reduction of reactive oxygen species and TNF-α levels and lowered expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia. Alternatively, particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury. Microinjections of chitosan/microRNA-124 particles significantly reduced the number of ED-1 positive macrophages after SCI. In summary, these results show that human MSC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for neural regeneration after spinal cord and peripheral nerve injury. The data also suggests that chitosan/microRNA-124 particles could be potential treatment technique to reduce neuroinflammation.

  • 207.
    Kolar, Mallappa K.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Regenerative effects of adipose-tissue-derived stem cells for treatment of peripheral nerve injuries2014In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 42, p. 697-701Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injuries are a common occurrence affecting the nerves found outside the central nervous system. Complete nerve transections necessitate surgical re-anastomosis, and, in cases where there is a significant gap between the two ends of the injured nerve, bridging strategies are required to repair the defect. The current clinical gold standard is the nerve graft, but this has a number of limitations, including donor site morbidity. An active area of research is focused on developing other techniques to replace these grafts, by creating tubular nerve-guidance conduits from natural and synthetic materials, which are often supplemented with biological cues such as growth factors and regenerative cells. In the present short review, we focus on the use of adipose-tissue-derived stem cells and the possible mechanisms through which they may exert a positive influence on peripheral nerve regeneration, thereby enabling more effective nerve repair.

  • 208.
    Kolar, Mallappa K
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The therapeutic effects of human adipose derived stem cells in a rat cervical spinal cord injury model2014In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, no 14, p. 1659-1674Article in journal (Refereed)
    Abstract [en]

    Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only capable of limited sprouting. In this study we investigated the effects of adult human adipose derived stem cells (ASC) on axonal regeneration following transplantation into the injured rat cervical spinal cord. ASC did not induce activation of astrocytes in culture and supported neurite outgrowth from adult rat sensory DRG neurons. After transplantation into the lateral funiculus 1mm rostral and caudal to the cervical C3-C4 hemisection, ASC continued to express BDNF, VEGF and FGF-2 for 3 weeks but only in animals treated with cyclosporine A. Transplanted ASC stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone with some terminal arborisations reaching the caudal spinal cord. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure of the lesion scar with numerous astrocytic processes extended into the middle of the trauma zone in a chain-like pattern and in close association with regenerating axons. The density of the astrocytic network was also significantly decreased. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the activity of OX42-positive microglial cells was markedly reduced. However, ASC did not support recovery of forelimb function. The results suggest that transplanted ASC can modify the structure of the glial scar and stimulate axonal sprouting.

  • 209.
    Kolar, Mallappa Kadappa
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Itte, Vinay N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kelk, Peyman
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The neurotrophic effects of different human dental mesenchymal stem cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12605Article in journal (Refereed)
  • 210.
    Kvam Sorgendal, Astrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    A Study of the Interaction betweenHuman Adipose Stem cells andBreast Cancer MCF-7 Cells.2014Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 211.
    Lindman, Rolf
    et al.
    University Hospital, Malmö.
    Paulin, Gunnar
    University Hospital, Linköping.
    Stål, Per S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Morphological characterization of the levator veli palatini muscle in children born with cleft palates2001In: The Cleft Palate-Craniofacial Journal, ISSN 1055-6656, E-ISSN 1545-1569, Vol. 38, no 5, p. 438-448Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to analyze, morphologically and biochemically, one of the soft palate muscles, the levator veli palatini (LVP), in children born with cleft palate.

    SUBJECTS AND METHODS: Biopsies were obtained from nine male and three female infants in connection with the early surgical repair of the hard and soft palate. Samples from five adult normal LVP muscles were used for comparison. The muscle morphology, fiber type and myosin heavy chain (MyHC) compositions, capillary supply, and content of muscle spindles were analyzed with different enzyme-histochemical, immunohistochemical, and biochemical techniques.

    RESULTS: Compared with the normal adult subjects, the LVP muscle from the infantile subjects with cleft had a smaller mean fiber diameter, a larger variability in fiber size and form, a higher proportion of type II fibers, a higher amount of fast MyHCs, and a lower density of capillaries. No muscle spindles were observed. Moreover, one-third of the biopsies from the infantile subjects with cleft LVP either lacked muscle tissue or contained only a small amount.

    CONCLUSIONS: The LVP muscle from children with cleft palate has a different morphology, compared with the normal adult muscle. The differences might be related to different stages in maturation of the muscles, changes in functional demands with growth and age, or a consequence of the cleft. The lack of contractile tissue in some of the cleft biopsies offers one possible explanation to a persistent postsurgical velopharyngeal insufficiency in some patients, despite a successful surgical repair.

  • 212.
    Lindman, Rolf
    et al.
    Malmö University Hospital.
    Stål, Per S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Abnormal palatopharyngeal muscle morphology in sleep-disordered breathing2002In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 195, no 1, p. 11-23, Article Number: PII S0022-510X(01)00676-1Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to investigate whether histopathological changes can be detected in two soft palate muscles, the palatopharyngeus and the uvula, in 11 patients with long duration of sleep-disordered breathing (SDB). Muscle samples were collected from patients undergoing uvulo-palatopharyngoplasty (UPPP). Reference samples from the corresponding areas were obtained at autopsy from five previously healthy subjects. Muscle morphology, fibre type and myosin heavy chain (MyHC) compositions were analysed with enzyme-histochemical, immunohistochemical and biochemical techniques. The muscle samples from the patients, and especially those from the palatopharyngeus, showed several morphological abnormalities. The most striking findings were (i) increased amount of connective tissue, (ii) abnormal variability in fibre size, (iii) increased proportion of small-sized fibres, (iv) alterations in fibre type and MyHC compositions, (v) increased frequency of fibres containing developmental MyHC isoforms. Our findings point towards a pathological process of denervation and degeneration in the patient samples. Conclusively, the morphological abnormalities suggest a neuromuscular disorder of the soft palate in SDB patients.

  • 213.
    Lindström, Mona
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Satellite cells in human skeletal muscle: molecular identification quantification and function2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Skeletal muscle satellite cells located between the plasma membrane and the basal lamina of muscle fibres, could for many years, only be studied in situ by electron microscopy. The introduction of immunohistochemistry and the discovery of molecular markers of satellite cells then made them accessible for light microscopic studies and a wealth of information is today available. Satellite cells are myogenic stem cells that can be activated from a quiescent state to proliferate for self-renewal or differentiate into myogenic cells. The satellite cells are involved in muscle growth during fetal and postnatal development and play a key role in repair and regeneration of damaged muscle fibres. The satellite cells are also essential for muscle fibre hypertrophy and maintenance of muscle mass in the adult. When the present thesis was initiated, studies on satellite cells in human skeletal muscle relied on the neuronal cell adhesion molecule (NCAM) as a marker for satellite cell identification. The results from different studies varied markedly. Therefore the aims of the present thesis were i) to develop a highly reliable method using light microscopy for satellite cell identification and quantification in biopsies of human skeletal muscle in normal and pathological conditions. A molecular marker for the myofibre basal lamina or plasma membrane to enhance the reliability of myonuclei and satellite cell identification were to be included. Furthermore unbiased morphometric methods should be used in the quantification process. ii) to evaluate which molecular markers which had been described for satellite cell and stem cell identification in different cell states (quiescence, activated or differentiated) are the most useful for studies on human skeletal muscle. iii) to further explore the function and heterogeneity of satellite cells with respect to different markers in human skeletal muscle by studying the effects of strength-training, intake of anabolic substances and pathological conditions.

    A new immunofluorescence method was developed where in the same tissue section, two satellite cell markers, the basal lamina and nuclei were monitored. From the evaluation of different markers it was found that both NCAM and Pax7 identified the majority of satellite cells but that both markers were needed for reliable identification. The members of the myogenic regulatory family were evaluated and by using the new method MyoD and myogenin were found to be useful markers to identify activated and differentiated satellite cells. Upon re-examination of biopsies from power-lifters, power-lifters using anabolic substances and untrained subjects it was observed that the new results on satellite cell frequency were significantly different from those obtained when using staining for NCAM and nuclei alone. In addition three subtypes of satellite cells (94.4% NCAM+/Pax7+, 4.2% NCAM+/Pax7 and 1.4% NCAM/Pax7+) were observed. Thus the multiple marker method gave more information about satellite cells heterogeneity in human muscle and we propose that this is more reliable than previous methods. Low numbers of MyoD or myogenin stained satellite cells were observed in both untrained and strength trained subjects. Other markers such as DLK1/FA1, a member of the EGF-like family and c-Met, the receptor for hepatocyte growth factor showed that satellite cell heterogeneity in human muscle is far greater than previously shown. Furthermore, new evidence is presented for so called fibre splitting observed in hypertrophic muscle fibres to be due to defect regeneration of partially damaged fibres.

  • 214.
    Lindström, Mona
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Satellite cell heterogeneity with respect to expression of MyoD, myogenin, Dlk1 and c-Met in human skeletal muscle: application to a cohort of power lifters and sedentary men2010In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 134, no 4, p. 371-385Article in journal (Refereed)
    Abstract [en]

    Human satellite cells (SCs) are heterogeneous with respect to markers for their identification in the niche between the muscle fibre plasma membrane and its basal lamina. We have previously shown that, in biopsies from highly competitive power lifters, power lifters with long-term use of anabolic steroids and a population of healthy sedentary men, antibodies against the neuronal cell adhesion molecule (NCAM) and the paired box transcription factor Pax7 together label 94% of the SCs, NCAM alone labels 4% and Pax7 alone labels 1%. In the present study, we have further studied these biopsies with four markers related to SC activation and differentiation. Our study unequivocally shows that staining for MyoD and myogenin are present in nuclei of SCs and of myoblasts and myotubes in areas of muscle fibre regeneration. Staining for c-Met was observed in a proportion of Pax7+ SCs. However, widespread labelling of the sarcolemma precluded the quantification of c-Met+/Pax7+ SCs and the use of c-Met as a reliable SC marker. Pax7+ SCs labelled by anti-Delta like1 (Dlk1) were present in all samples but in variable proportions, whereas muscle progenitor cells related to repair were Dlk1⁻. Staining for Dlk1 was also observed in Pax7⁻ interstitial cells and in the cytoplasm of some small muscle fibres. Interestingly, the proportion of Dlk1+/Pax7+ SCs was significantly different between the groups of power lifters. Thus, our study confirms that human SCs show marked heterogeneity and this is discussed in terms of SC activation, myonuclei turnover, muscle fibre growth and muscle fibre damage and repair.

  • 215.
    Lindström, Mona
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    New multiple labelling method for improved satellite cell identification in human muscle: application to a cohort of power-lifters and sedentary men.2009In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 132, no 2, p. 141-57Article in journal (Refereed)
    Abstract [en]

    Presently applied methods to identify and quantify human satellite cells (SCs) give discrepant results. We introduce a new immunofluorescence method that simultaneously monitors two SC markers (NCAM and Pax7), the basal lamina and nuclei. Biopsies from power-lifters, power-lifters using anabolic substances and untrained subjects were re-examined. Significantly different results from those with staining for NCAM and nuclei were observed. There were three subtypes of SCs; NCAM(+)/Pax7(+) (94%), NCAM(+)/Pax7(-) (4%) and NCAM(-)/Pax7(+) (1%) but large individual variability existed. The proportion of SCs per nuclei within the basal lamina of myofibres (SC/N) was similar for all groups reflecting a balance between the number of SCs and myonuclei to maintain homeostasis. We emphasise that it is important to quantify both SC/N and the number of SCs per fibre. Our multiple marker method is more reliable for SC identification and quantification and can be used to evaluate other markers of muscle progenitor cells.

  • 216.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Human muscle spindles: complex morphology and structural organisation2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Muscle spindles are skeletal muscle mechanoreceptors that mediate the stretch reflex and provide axial and limb position information to the central nervous system. They have been proposed to play a major role in the pathophysiology of muscle pain. Knowledge about the normal human muscle spindles is needed in order to understand their role in muscle disease or dysfunction.

    The aim of this study was to investigate the fiber content and MyHC composition of the muscle spindles in the human biceps brachii (BB) and deep muscles of the neck (DN); to determine whether there are age-related changes in human muscle spindles with respect to structure and MyHC composition; to investigate the distribution of SERCA isoforms and to evaluate whether there is a coordinated expression of SERCA and MyHC isoforms in intrafusal fibers. The myosin heavy chain (MyHC) content correlates to contraction velocity and force and the sarcoplasmic reticulum Ca2+ ATPase (SERCA) is a major determinant of muscle fiber relaxation velocity.

    Muscle specimens obtained from young and old subjects were serially sectioned and the pattern of distribution of different proteins along the length of the intrafusal fibers was revealed by immunocytochemistry. The MyHC content of single muscle spindles was assessed with SDS-PAGE and immunoblots.

    There were clear differences between BB and DN with regard to the morphology and MyHC composition of muscle spindles. Virtually each muscle spindle in the BB, but not in the DN, had a unique allotment of numbers of bag1, bag2 and chain fibers. In DN, a number of muscle spindles lacked either bag1 or bag2 fibers. Four major MyHC isoforms (MyHCI, IIa, α-cardiac and intrafusal) were detected by SDS-PAGE. In both BB and DN, immunocytochemistry revealed co-expression of several MyHC isoforms in each intrafusal fiber and regional heterogeneity. Both nuclear bag1 and bag2 fibers contained slow tonic MyHC uniformly and MyHCI, α-cardiac, embryonic and fetal with regional variations. Nuclear chain fibers contained MyHCIIa, embryonic and fetal and in the BB also MyHCIIx.

    The total number of intrafusal fibers per spindle decreased significantly with aging, due to a significant reduction in the number of nuclear chain fibers. The patterns of MyHC expression were also affected by aging.

    The bag1 fibers predominantly contained both SERCA isoforms in the encapsulated region. The bag2 fibers were more heterogeneous in their SERCA composition and 16-27% of them lacked both isoforms. Chain fibers contained SERCA1. There was a poor correlation between the MyHC and SERCA isoforms in nuclear bag fibers, whereas a strong correlation existed between MyHCIIa and SERCA1 in the nuclear chain fibers.

    Human muscle spindles, each being unique, proved to be more complex than anticipated. The clear differences shown between the BB and DN muscle spindles suggest functional specialization in the control of movement among different human muscles. Aging apparently had profound effects on intrafusal fiber content and MyHC composition. The age-related changes in muscle spindle phenotype may reflect deterioration in sensory and motor innervation and are likely to have a detrimental impact on motor control in the elderly.

  • 217.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Different impact of ALS on laminin isoforms in human extraocular muscles versus limb muscles2011In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 52, no 7, p. 4842-4852Article in journal (Refereed)
    Abstract [en]

    Purpose. To determ ine the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the laminin isoform composition of the basement membranes (BMs) in EOMs and limb muscles from donors with ALS.

    Methods. Muscle samples collected at autopsy from ALS donors and from transgenic mice overexpressing human SOD1 mutations (D90A or G93A), and age-matched controls were analyzed with immunohistochemistry using antibodies against laminin chain α2 (Lnα2), Lnα4, Lnα5, Lnβ1, Lnβ2 and Lnγ1. Neuromuscular junctions (NMJs) were identified with α-bungarotoxin.

    Results. Lnα2, the hallmark chain of skeletal muscle, and Lnβ2 were absent or partially absent from the BMs in a variable number of muscle fibers in most of the ALS EOMs. Three ALS donors showed dramatic decrease in the levels of these chains around their muscle fibers and NMJs. Changes in Lnα2 were not age-related and were also present in EOMs of ALS mouse models. Lnα4 was preserved in the majority of NMJs in EOM but absent in the majority of NMJs in limb muscle of ALS. The BMs around muscle fibers, NMJs, nerves and blood vessels of the majority of EOMs of ALS donors had rather normal appearance and laminin composition, but heterogeneity was observed among EOM samples of individual ALS donors and between ALS donors.

    Conclusions. The present study showed distinct impact of ALS on EOMs as compared to limb muscles. The EOMs maintained a normal laminin composition in their NMJs which may be instrumental for the fact that they are not typically affected in ALS.

  • 218.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Distinct changes in synaptic protein composition at neuromuscular junctions of extraocular muscles versus limb muscles of ALS donors2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, p. e57473-Article in journal (Refereed)
    Abstract [en]

    The pathophysiology of amyotrophic lateral sclerosis (ALS) is very complex and still rather elusive but in recent years evidence of early involvement of the neuromuscular junctions (NMJs) has accumulated. We have recently reported that the human extraocular muscles (EOMs) are far less affected than limb muscles at the end-stage of ALS from the same donor. The present study aimed to compare the differences in synaptic protein composition at NMJ and in nerve fibers between EOM and limb muscles from ALS donors and controls. Neurofilament light subunit and synaptophysin decreased significantly at NMJs and in nerve fibers in limb muscles with ALS whereas they were maintained in ALS EOMs. S100B was significantly decreased at NMJs and in nerve fibers in both EOMs and limb muscles of ALS donors, but other markers confirmed the presence of terminal Schwann cells in these NMJs. p75 neurotrophin receptor was present in nerve fibers but absent at NMJs in ALS limb muscles. The EOMs were able to maintain the integrity of their NMJs to a very large extent until the end-stage of ALS, in contrast to the limb muscles. Changes in Ca2+ homeostasis, reflected by altered S100B distribution, might be involved in the breakdown of nerve-muscle contact at NMJs in ALS.

  • 219.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Eriksson, Per-Olof
    Umeå University, Faculty of Medicine, Department of Odontology, Clinical Oral Physiology.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Fiber content and myosin heavy chain composition of muscle spindles in aged human biceps brachii2005In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 53, no 4, p. 445-454Article in journal (Refereed)
    Abstract [en]

    The present study investigated potential age-related changes in human muscle spindles with respect to the intrafusal fiber-type content and myosin heavy chain (MyHC) composition in biceps brachii muscle. The total number of intrafusal fibers per spindle decreased significantly with aging, due to a significant reduction in the number of nuclear chain fibers. Nuclear chain fibers in old spindles were short and some showed novel expression of MyHC alpha-cardiac. The expression of MyHC alpha-cardiac in bag1 and bag2 fibers was greatly decreased in the A region. The expression of slow MyHC was increased in nuclear bag1 fibers and that of fetal MyHC decreased in bag2 fibers whereas the patterns of distribution of the remaining MyHC isoforms were generally not affected by aging. We conclude that aging appears to have an important impact on muscle spindle composition. These changes in muscle spindle phenotype may reflect an age-related deterioration in sensory and motor innervation and are likely to have an impact in motor control in the elderly.

  • 220.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Eriksson, Per-Olof
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Myosin heavy chain composition of muscle spindles in human biceps brachii2002In: Histochem Cell Biol, Vol. 50, no 2, p. 171-184Article in journal (Refereed)
    Abstract [en]

    Data on the myosin heavy chain (MyHC) composition of human muscle spindles are scarce in spite of the well-known correlation between MyHC composition and functional properties of skeletal muscle fibers. The MyHC composition of intrafusal fibers from 36 spindles of human biceps brachii muscle was studied in detail by immunocytochemistry with a large battery of antibodies. The MyHC content of isolated muscle spindles was assessed with SDS-PAGE and immunoblots. Four major MyHC isoforms (MyHCI, IIa, embryonic, and intrafusal) were detected with SDS-PAGE. Immunocytochemistry revealed very complex staining patterns for each intrafusal fiber type. The bag(1) fibers contained slow tonic MyHC along their entire fiber length and MyHCI, alpha-cardiac, embryonic, and fetal isoforms along a variable part of their length. The bag(2) fibers contained MyHC slow tonic, I, alpha-cardiac, embryonic, and fetal isoforms with regional variations. Chain fibers contained MyHCIIa, embryonic, and fetal isoforms throughout the fiber, and MyHCIIx at least in the juxtaequatorial region. Virtually each muscle spindle had a different allotment of numbers of bag(1), bag(2) and chain fibers. Taken together, the complexity in intrafusal fiber content and MyHC composition observed indicate that each muscle spindle in the human biceps has a unique identity.

  • 221.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Höglund, Anna-Stina
    Department of Neurosciences, Uppsala University, Uppsala, Sweden.
    Karlsson, Patrick
    Centre for Image Analyses, Uppsala University, Uppsala, Sweden.
    Lindblad, Joakim
    Centre for Image Analyses, University of Agricultural Sciences, Uppsala, Sweden.
    Qaisar, Rizwan
    Department of Neurosciences, Uppsala University, Uppsala, Sweden.
    Aare, Sudhakar
    Department of Neurosciences, Uppsala University, Uppsala, Sweden.
    Bengtsson, Ewert
    Centre for Image Analyses, Uppsala University, Uppsala, Sweden.
    Larsson, Lars
    Department of Neurosciences, Uppsala University, Uppsala, Sweden.
    Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100,000-fold difference in body size.2009In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 94, no 1, p. 117-129Article in journal (Refereed)
    Abstract [en]

    This comparative study of myonuclear domain (MND) size in mammalian species representing a 100,000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the beta/slow (type I; r = 0.84, P < 0.001) and the fast IIA MyHC isoform (r = 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.

  • 222.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    A novel type of multiterminal motor endplate in human extraocular muscles2018In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 1, p. 539-548Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the relation between type of motor endplate, acetylcholine receptor (AChR) subunit composition, and fiber types in human extraocular muscles (EOMs).

    Methods: EOM samples collected from subjects aged 34 to 82 years were serially sectioned and processed for immunohistochemistry, with specific antibodies against different myosin heavy chain (MyHC) isoforms, neurofilament, synaptophysin, and adult epsilon (ε) and fetal gamma (γ) AChR subunits as well as α-bungarotoxin.

    Results: A novel type of motor endplate consisting of large, multiterminal en plaque endings was found in human EOMs, in addition to the previously well-described single en plaque and multiple en grappe endplates. Such novel endplates were abundant but exclusively observed in myofibers lacking MyHC slow and fast IIa but containing MyHC extraocular (MyHCeom), isoforms. Multiple en grappe endings were found only in myofibers containing MyHC slow-tonic isoform and contained fetal γ AChR subunit. Adult ε and fetal γ AChR subunits, alone or combined, were found in the multiterminal endplates. Distinct AChR subunits were present in adjacent motor endplates of a given myofiber containing MyHCeom.

    Conclusions: Human EOMs have a more complex innervation pattern than previously described, comprising also a novel type of multiterminal motor endplate present in myofibers containing MyHCeom. The heterogeneity in AChR subunit composition in a given myofiber suggests the possible presence of polyneuronal innervation in human EOMs.

  • 223.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Distribution of SERCA isoforms in human intrafusal fibers2003In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 120, no 4, p. 299-306Article in journal (Refereed)
    Abstract [en]

    The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is a membrane protein that plays a crucial role in muscle relaxation by transporting cytosolic Ca2+ into the lumen of the sarco/endoplasmic reticulum. In this study, the presence of SERCA1 and SERCA2 was investigated in human intrafusal fibers by immunocytochemistry. Nuclear bag1 fibers contained both SERCA1 and SERCA2 isoforms, with predominant staining seen with SERCA2 in the A and B regions. Most nuclear bag2 fibers also contained SERCA1 and SERCA2 isoforms and their coexistence frequently occurred in the A region. SERCA1 was present whereas SERCA2 was generally absent in the nuclear chain fibers. The staining intensity seen with the SERCA1 monoclonal antibody varied in the order of chain>bag1>bag2. The expression of SERCA1 isoform was found to correlate with the presence of fast myosin heavy chain (MyHC) isoform in nuclear chain fibers, whereas for nuclear bag fibers there was no such apparent correlation between patterns of expression of SERCA and MyHC isoforms. The phenotype revealed for the human bag fibers was very sophisticated and adapted to attain a very wide range of contraction and relaxation velocities.

  • 224.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Muscle spindles in the deep muscles of the human neck: a morphological and immunocytochemical study2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, no 2, p. 175-186Article in journal (Refereed)
    Abstract [en]

    Muscle spindle density is extremely high in the deep muscles of the human neck. However, there is a paucity of information regarding the morphology and immunoreactivity of these muscle spindles. The objective of this study was to investigate the intrafusal fiber content and to assess the myosin heavy chain (MyHC) composition of muscle spindles from human deep neck muscles. In addition to the conventional spindles containing bag(1), bag(2), and chain fibers (b(1)b(2)c spindle), we observed a number of spindles lacking bag(1) (b(2)c spindle) or bag(2) (b(1)c spindle) fibers. Both bag(1) and bag(2) fibers contained slow tonic MyHCs along their entire fiber length and MyHCI, MyHCIIa, embryonic, and alpha-cardiac MyHC isoforms along a variable length of the fibers. Fetal MyHC was present in bag(2) fibers but not in bag(1) fibers. Nuclear chain fibers contained MyHCIIa, embryonic, and fetal isoforms with regional variations. We also compared the present data with our previous results obtained from muscle spindles in human biceps brachii and the first lumbrical muscles. The allotment of numbers of intrafusal fibers and the MyHC composition showed some muscle-related differences, suggesting functional specialization in the control of movement among different human muscles.

  • 225.
    Liu, Jing-Xia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Willison, Hugh J
    Pedrosa-Domellof, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Immunolocalisation of GQ1b and related gangliosides in human extraocular neuromuscular junctions and muscle spindles2009In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 50, no 7, p. 3226-3232Article in journal (Refereed)
    Abstract [en]

    Purpose: To examine the distribution of anti-GQ1b, -GT1a and -GD1b antibody binding in human extraocular muscles (EOMs), axial and limb muscles and muscle spindles and thereby test the hypothesis that their distinctive ganglioside composition provides the molecular basis for selective involvement of EOMs and muscle spindles in Miller Fisher syndrome.

    Methods: Muscle samples from adult human EOMs, vastus lateralis, biceps brachii, lumbrical, psoas and deep muscles of the neck were processed for immunohistochemistry, with monoclonal antibodies against ganglioside GQ1b, GT1a and GD1b. Neuromuscular junctions (NMJs) were detected by a-bungarotoxin binding and by acetycholinesterase reaction.

    Results: The vast majority of motor endplates of human EOMs richly bound anti-GQ1b, -GT1a, and -GD1b ganglioside antibodies. Anti-GQ1b, -GT1a, and -GD1b ganglioside antibody bindings to NMJs in human limb and axial muscle were very scarce but the nerve terminals inside muscle spindles and in direct contact with intrafusal fibers were labeled with anti- GQ1b, -GT1a and -GD1b ganglioside antibodies.

    Conclusions: The abundant and synaptic-specific binding of anti-GQ1b, -GT1a, and -GD1b ganglioside antibodies and the rich capillary supply in the human EOMs may partly explain the selective paralysis of these muscles in Miller Fisher syndrome.

  • 226. Ljung, Björn-Ove
    et al.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Neurokinin 1-receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus. Studies on tennis elbow and medial epicondylalgia.2004In: Journal of Orthopaedic Research, ISSN 0736-0266, Vol. 22, no 2, p. 321-7Article in journal (Refereed)
    Abstract [en]

    There is no information on the sensory innervation at the flexor muscle origin at the medial epicondyle of the humerus and it is not known if substance P receptors (Neurokinin 1-receptors, NK1-R) are present in tendon insertions in general. In the present investigation, we have studied the muscle origin in patients suffering from medial epicondylalgia and tennis elbow. Immunohistochemistry and antibodies to substance P (SP) and CGRP as well as the general nerve marker PGP 9.5 were used. Specific immunoreactions were observed in nerve bundles and as free nerve fibers. The immunoreactive structures were partly seen in association with some of the blood vessels. The observations constitute a morphological correlate for the occurrence of nerve mediated effects in this region. By using immunohistochemistry and antibodies to NK1-R, the distribution of this receptor was studied at the insertion of the proximal tendon of the extensor carpi radialis brevis muscle at the lateral epicondyle. Specific immunoreactions were seen as varicose fibers occurring as single fibers or grouped into bundles, indicating that SP has effects in the nerves in this region. The results give further evidence for a possible neurogenic involvement in the pathophysiology of tennis elbow and in medial epicondylalgia.

  • 227.
    Lundberg, Simon
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Hansson, Magnus
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Natriuretic peptide expression in the heart of the TTR-ANP transgenic mouse-Comparison to the normal heart.2005In: Microscopy Research & Technique, ISSN 1059-910X, Vol. 68, no 2, p. 97-106Article in journal (Refereed)
    Abstract [en]

    The transgenic mice, TTR-ANP, carrying a fusion gene comprising the transthyretin promoter and the atrial natriuretic peptide (ANP) structural sequence, are known to have elevated ANP plasma levels as well as lowered blood pressure levels. On the other hand, it is not known whether these transgenic mice show changed natriuretic peptide (NP) expression patterns in the heart. Therefore, we examined the distribution of NPs in the myocardium and the conduction system of transgenic mice overexpressing ANP, as well as in wild-type littermates. The hearts were serially sectioned and processed for immunohistochemistry, with antisera against ANP and brain natriuretic peptide (BNP). Florescence microscopy was performed for qualitative analysis. Immunoreactivity for ANP and BNP was detected to a similar degree in the conduction system of both transgenic and wild-type mice. The nodal tissues never exhibited immunoreactions for ANP or BNP, whereas Purkinje fibers of the atrioventricular junctional tissue, bundle branches, and the peripheral Purkinje fiber network exhibited specific immunoreactivity. Atrial and ventricular myocytes of both transgenic and wild-type mice exhibited ANP and BNP to a similar extent. This is the first study examining the expression pattern of NPs in the cardiac conduction system of the mouse as well as the pattern of ANP and BNP expression in the conduction system of TTR-ANP transgenic mice and its wild-type siblings. The findings in this study suggest that ectopic ANP expression and release do not repress cardiac production of ANP.

  • 228.
    Ma, J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, L N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Karlsson, K
    Kellerth, J O
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, M
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Plexus avulsion and spinal cord injury increase the serum concentration of S-100 protein: an experimental study in rats.2001In: Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, ISSN 2000-656X, E-ISSN 2000-6764, Vol. 35, no 4, p. 355-9Article in journal (Refereed)
    Abstract [en]

    The possibility of using the presence of the glial-cell-derived protein S-100 in serum as a marker for neuronal damage caused by spinal cord injury and plexus avulsion injury was investigated in 144 adult rats. After a spinal cord injury had been induced at the thoracic level or a plexus avulsion injury at the lumbar level, blood samples were taken and analysed for S-100 protein by a monoclonal two-site immunoluminometric assay. The two types of neurotrauma changed the kinetics of serum S-100 in different ways. After spinal cord injury it rapidly increased and within 72 hours had reached a concentration about 5 times that of the control animals. Three peak concentrations occurred at 3, 12, and 72 hours, respectively, and differed significantly from those of the control group (p < 0.05). After six days the values had returned to normal. After lumbar plexus injury alone there was no significant increase in the concentration of S-100. These results suggest that the concentration of S-100 protein in serum may be used as an early diagnostic tool for detecting neuronal damage caused by spinal cord injury or plexus avulsion associated with damage to the root entry zone.

  • 229.
    Ma, J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, L N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, M
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kellerth, J O
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Delayed loss of spinal motoneurons after peripheral nerve injury in adult rats: a quantitative morphological study.2001In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 139, no 2, p. 216-23Article in journal (Refereed)
    Abstract [en]

    The existence of retrograde cell death in sensory dorsal root ganglion (DRG) cells after peripheral nerve injury is well established. However, with respect to retrograde motoneuron death after peripheral nerve injury, available data are conflicting. This may partly be due to the cell counting techniques used. In the present study, quantitative morphometric methods have been used to analyse retrograde motoneuron death induced by spinal nerve injury in adult rats. For comparison, DRG cells were also included in the study. The C7 spinal nerve was transected about 10 mm distal to the DRG and exposed to the fluorescent tracer fast blue in order to retrogradely label the spinal motoneurons and DRG cells of the C7 segment. At 1-16 weeks postoperatively, the nuclei of fast-blue-labelled C7 motoneurons and DRG cells were counted in consecutive 50-microm-thick serial sections. For comparison, the physical disector technique and measurements of neuronal density were also used to calculate motoneuron number. The counts of fast-blue-labelled motoneurons revealed a delayed motoneuron loss amounting to 21% and 31% after 8 and 16 weeks, respectively (P<0.001). The remaining motoneurons exhibited 20% (P<0.05) soma atrophy. Using the physical disector technique, the motoneuron loss was 23% (P<0.001) after 16 weeks. Calculations of neuronal density in Nissl-stained sections failed to reveal any motoneuron loss, although after correction for shrinkage of the ventral horn a 14% (P<0.001) motoneuron loss was found. The fast-blue-labelled DRG neurons displayed 51% (P<0.001) cell loss after 16 weeks, and the remaining cells showed 22% (P<0.001) soma atrophy. In summary, cervical spinal nerve injury induces retrograde degeneration of both motoneurons and DRG cells. However, to demonstrate the motoneuron loss adequate techniques for cell counts have to be employed.

  • 230.
    Ma, Jianjun
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Early nerve repair after injury to the postganglionic plexus: an experimental study of sensory and motor neuronal survival in adult rats.2003In: Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, ISSN 2000-656X, E-ISSN 2000-6764, Vol. 37, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The optimal time for brachial plexus nerve repair is debatable. In this study we examined whether early re-establishment of neurotrophic support from the periphery might reduce neuronal loss. In 14 adult rats, the C7 spinal nerve was transsected. All sensory cells of the dorsal root ganglion and spinal motor neurons projecting into the C7 nerve were labelled retrogradely. The proximal and distal portions of the C7 nerve were then reanastomosed by either primary repair or by a vascularised or conventional ulnar nerve graft. At 16 weeks postoperatively, the nerve repair had significantly reduced the loss of both sensory and motor C7 neurons. Most striking was that a 30% motor neuronal loss in the control was almost eliminated by early nerve repair. In the grafted animals, half of the surviving neurons had regenerated through the graft, with no difference between vascularised and conventional nerve grafts. These results suggest that early surgical intervention may promote neuronal survival and regeneration after injuries to the brachial plexus.

  • 231.
    Malm, Christer
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Exercise immunology: the current state of man and mouse.2004In: Sports Medicine, ISSN 0112-1642, Vol. 34, no 9, p. 555-66Article in journal (Refereed)
    Abstract [en]

    The mechanisms governing the body's response to physical exercise have been investigated from various perspectives including metabolism, nutrition, age and sex. Increased attention to the immune system during recent decades is reflected by a rapidly growing number of publications in the field. This article highlights the most recent findings and only briefly summarises more basic concepts already reviewed by others. Topics include Th1/Th2 cytokine balance, inoculation time, age and immune compensation. Some less investigated areas are discussed including studies in children, the environment and dendritic cells. Because physical exercise enhances some aspects and suppresses other aspects of immunity, the biological significance of alterations in the immune system are unknown. So far, no link between immunological alterations and infection rate has been established and infection after strenuous physical exercise is equally likely to be the result of exercising with an already established rather than a new infection. If there is an increased risk for infections with increased exercise duration and intensity, why do overtrained athletes not display the greatest risk for upper respiratory tract infections? Increased knowledge on immune system modulations with physical exercise is relevant both from a public health and elite athlete's point of view.

  • 232.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Susceptibility to infections in elite athletes: the S-curve2005In: Scandinavian journal of medicine & science in sports, ISSN 0905-7188, Vol. 16, no 1, p. 4-6Article in journal (Other academic)
    Abstract [en]

    The susceptibility to upper respiratory tract infections (URTIs) after physical exercise has been described with a J-shaped curve, suggesting protection from infections with moderate exercise and increased risk for URTI`s in elite athletes. Several factors such as time of inoculation, previous infections, pathogen exposure, other stressors than exercise etc. can influence infection outcome. Observed infections in athletes can, therefore, be either the result of increased susceptibility to a novel pathogen, or more severe symptoms of an already established infection. Moreover, the definitions of "strenuous" exercise and "elite" athletes are equivocal, making comparisons between studies difficult.

    Because absence of infections is inevitable to become and maintain status as an elite athlete, it is suggested that there is an S-shaped relationship between exercise load and risk of infections. To become an elite athlete one has to possess state-of-the-art physique, including an immune system able to withstand infections even during severe physiological and psychological stress.

  • 233.
    Malm, Christer
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Celsing, F
    Friman, G
    Physical activity both enhances and depresses the immune system2005In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 102, no 11, p. 867-873Article, book review (Other (popular science, discussion, etc.))
  • 234.
    Malm, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Celsing, F
    Friman, G
    Physical activity both enhances and depresses the immune system [Fysisk aktivitet både stimulerar och hämmar immunförsvaret]2005In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, ISSN 237205, Vol. 102, no 11, p. 867-873Article, book review (Other (popular science, discussion, etc.))
  • 235.
    Malm, Christer
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Celsing, Fredrik
    Friman, Göran
    Immune defense is both stimulated and inhibited by physical activity2005In: Läkartidningen, ISSN 0023-7205, Vol. 102, no 11, p. 867-8, 870, 873Article in journal (Other academic)
    Abstract [sv]

    Physical exercise may enhance some and depress other immune functions. The biological importance of these changes is not fully elucidated. Acute endurance exercise results in a relatively large redistribution of leukocytes between circulating blood and other tissues, as well as an increase in circulating cytokines. Some of these changes have been related to energy metabolism. A temporal correlation has been observed between altered immune functions and resistance to infections. A post-exercise infection can be either the result of a pre-exercise, sub-clinical infection amplified by the performed work or a novel infection, acquired during a period of decreased immune function shortly after exercise. Animal experiments have demonstrated that the susceptibility to infections after exercise depends on exercise intensity and duration, type of pathogen and time of inoculation. Exercise before inoculation with some bacterial agents can enhance resistance to infection, while exercise during an ongoing viral or bacterial infection worsens symptoms and enhances the risk for complications. Most studies demonstrate a deleterious effect of physical exercise in conjunction with infectious episodes.

  • 236.
    Malm, Christer
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Ekblom, Ö
    Ekblom, B
    Immune system alteration in response to increased physical training during a five day soccer training camp.2004In: International journal of sports medicine, ISSN 0172-4622, Vol. 25, no 6, p. 471-6Article in journal (Refereed)
    Abstract [en]

    Leukocyte and monocyte subpopulations were investigated in ten elite male soccer players before and after a 5-day training camp. It was hypothesized that with increased training intensity and duration, the immune system would show signs of depression. Blood samples were taken at rest before and after the training camp and cell surface antigens were investigated by four-colour flow cytometry. After five days of intensified training, there was a significant decrease in the number of T helper, T cytotoxic and B cells, the expression of CD11 b on leukocytes increased and the NK cell population did not change significantly. It is concluded that after a period of intensified training, soccer players may experience decreased T and B cell numbers in circulation, possibly affecting their capability to activate the immune system and resist infections. However, in contrast to the acute decrease in the number of circulating NK cells commonly observed after physical exercise, no change in this cell population was observed at rest after a period of intensified physical training. Exercise-induced immunological changes were highly differentiated between different leukocyte subpopulations.

  • 237.
    Malm, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lindberg, Ann-Sofie
    Brandmannens fysiska förmåga: Delrapport 2 - Fysiologiska tester2005Report (Other (popular science, discussion, etc.))
    Abstract [sv]

    En viktig faktor för utgången av en räddningsinsats är räddningspresonalens fysiska prestationsförmåga. Det är därför av stor vikt att de fysiologiska krav som en brandman ska uppfylla är relevanta för yrkets arbetsuppgifter. Lika viktigt är det att resultaten på de tester av fysisk arbetskapacitet som genomförs inom Räddningstjänsten är direkt relaterade till arbetsprestation.

    Syftet med denna studie var att ta fram ett antal enkelt genomförbara tester av fysisk arbetskapacitet som är direkt relaterade till prestationen på de tyngsta arbetsmomenten inom Räddningstjänsten (se Brandmannens fysiska förmåga Delrapport 1 - Typinsatser). Fysisk prestationsförmåga kan var en begränsande faktor för dessa arbetuppgifters utförande.

    Andra möjliga begränsade faktorer vid dessa arbetsuppgifter så som psykologiska faktorer, teknisk kompetens eller logisk förmåga har inte behandlats i denna studie.

    Sammanlagt har 244 mätvariabler registrerats på 38 individer (9272 observationer) i samband med 7 arbetsuppgifter relaterade till Räddningstjänst. Individerna var indelade i 4 grupper: Heltidsbrandmän, Deltidsbrandmän, Män och Kvinnor. De arbetsuppgifter som studerats är: Håltagning i yttertak, Losstagning ur bil, Slangkorgsbärning i terräng, Slangkorgsbärning i trapphus, Slangdragning, Rivning av innertak och Docksläpning.

    Resultat blev att prestationen på 5 av de 7 studerade arbetsuppgifter kan beskrivas med hjälp av 8 relativt enkelt genomförbara mätningar. Dessa mätningar är: Kroppslängd, Kroppsvikt, Maximal handgreppsstyrka, Bänkpress, Lyft till hakan, Stående längdhopp, Löpning 3000 m och Rodd 500 m. Resultaten visar även att maximal syreupptagning kan bestämmas med relativt stor säkerhet från dessa 8 mätningar. Inga av dessa resultat diskriminerar någon av de studerade grupperna.

    Rullbandstest (AFS 1995:1) och Cykeltest 200 W underskattar kvinnors och överskattar mäns aeroba arbetskapacitet och bör därför inte användas som mått på detta, utan även i fortsättningen användas enbart för medicinsk bedömning.

    Resultaten på testerna kan ligga till grund för en relevant och objektiv bedömning av personers fysiska prestationsförmåga vid nyrekrytering och återtestning av personal inom Räddningstjänsten.

  • 238.
    Malm, Christer
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Sjödin, Bertil
    Sjöberg, Berit
    Lenkei, Rodica
    Renström, Per
    Lundberg, Ingrid E
    Ekblom, Björn
    Leukocytes, cytokines, growth factors and hormones in human skeletal muscle and blood after uphill or downhill running.2004In: The Journal of physiology, ISSN 0022-3751, Vol. 556, no Pt 3, p. 983-1000Article in journal (Refereed)
    Abstract [en]

    Muscular adaptation to physical exercise has previously been described as a repair process following tissue damage. Recently, evidence has been published to question this hypothesis. The purpose of this study was to investigate inflammatory processes in human skeletal muscle and epimysium after acute physical exercise with large eccentric components. Three groups of subjects (n= 19) performed 45 min treadmill running at either 4 deg (n= 5) or 8 deg (n= 9) downhill or 4 deg uphill (n= 5) and one group served as control (n= 9). One biopsy was taken from each subject 48 h post exercise. Blood samples were taken up to 7 days post exercise. Compared to the control group, none of the markers of inflammation in muscle and epimysium samples was different in any exercised group. Only subjects in the Downhill groups experienced delayed onset of muscle soreness (DOMS) and increased serum creatine kinase activity (CK). The detected levels of immunohistochemical markers for T cells (CD3), granulocytes (CD11b), leukaemia inhibitory factor (LIF) and hypoxia-inducible factor 1beta (HIF-1beta) were greater in epimysium from exercised subjects with DOMS ratings >3 (0-10 scale) compared to exercised subjects without DOMS but not higher than controls. Eccentric physical exercise (downhill running) did not result in skeletal muscle inflammation 48 h post exercise, despite DOMS and increased CK. It is suggested that exercise can induce DOMS by activating inflammatory factors present in the epimysium before exercise. Repeated physical training may alter the content of inflammatory factors in the epimysium and thus reduce DOMS.

  • 239.
    Malm, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Yu, Ji-Guo
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Exercise-induced muscle damage and inflammation: re-evaluation by proteomics2012In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 138, no 1, p. 89-99Article in journal (Refereed)
    Abstract [en]

    Using proteomics combined with immunohistochemistry (IHC), we re-evaluated our previous hypothesis that voluntary eccentric exercise does not result in inflammation or necrosis while it does lead to muscular adaptation/remodeling through Z-band related proteins. Muscle biopsies from m. vastus lateralis were taken from five control and five exercised subjects 48 h after 45 min of downhill running. General muscle morphology was examined using histology and histochemistry. Proteomics was used to reveal protein profiles and novel proteins. IHC with specific antibody against three Z-band related proteins identified by proteomics was also performed. General morphology showed no muscle degeneration or inflammation in any exercised biopsy. Proteomics revealed that out of 612 individual protein spots, the exercised biopsy presented three proteins with significant (p < 0.05) higher expression ratio and four proteins of lower ratio compared to controls. Four of the proteins desmin, actin, Rab-35 and LDB3 are Z-band related; the former two have long been the focus of interest and were found to be up-regulated in the study; the latter two are Z-band assembly/stabilization protein and were for the first time observed to be down-regulated in exercised muscles. The other three proteins are related with either cellular metabolism or calcium homeostasis and none is related with muscle necrosis or inflammation. IHC observations that both desmin and actin were increased whereas LDB3 was completely absent in some focal areas are consistent with proteomic results and with our previous observations. The results of the study confirmed our previous findings and therefore strengthened the hypothesis that voluntary eccentric exercise does not cause human muscle necrosis or inflammation; instead, muscular remodeling occurs specifically through Z-band related proteins.

  • 240.
    Mantovani, Cristina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Mahay, Daljeet
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    Shawcross, Susan G
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins2010In: Regenerative medicine, ISSN 1746-076X, Vol. 5, no 3, p. 403-410Article in journal (Refereed)
    Abstract [en]

    Aims: PNS myelin is formed by Schwann cells (SCs). In this study, we applied an in vitro model to study myelin formation, using bone marrow mesenchymal stem cells and adipose-derived stem cells differentiated into SC-like cells and co-cultured with dissociated adult dorsal root ganglia neurons.

    Methods: Immunocytochemistry, reverse transcription-PCR and western blotting techniques were used to investigate the expression of myelin proteins at both the transcriptional and translational level.

    Results: Transcripts for protein zero, peripheral myelin protein 22 and myelin basic protein were detected in differentiated stem cells following co-culture with neuronal cells. Furthermore, protein zero, peripheral myelin protein 22 and myelin basic proteins were recognized in the co-cultures. These results were consistent with immunostaining of myelin proteins and with observation by electron microscopy.

    Conclusion: Both types of adult stems cells differentiated into SC-like cells have potential to myelinate neuronal cells during regeneration, being functionally identical to SCs of the PNS.

  • 241.
    Mantovani, Cristina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. University of Manchester.
    Raimondo, Stefania
    University of Turin.
    Haneef, Maryam S.
    University of Manchester.
    Geuna, Stefano
    University of Turin.
    Terenghi, Giorgio
    University of Manchester.
    Shawcross, Susan G.
    University of Manchester.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages2012In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 318, no 16, p. 2034-2048Article in journal (Refereed)
    Abstract [en]

    Adult mesenchymal stem cells have self-renewal and multiple differentiation potentials, and play important roles in regenerative medicine. However, their use may be limited by senescence or age of the donor, leading to changes in stem cell functionality. We investigated morphological, molecular and functional differences between bone marrow-derived (MSC) and adipose-derived (ASC) stem cells isolated from neonatal, young and old rats compared to Schwann cells from the same animals. Immunocytochemistry, RT-PCR, proliferation assays, western blotting and transmission electron microscopy were used to investigate expression of senescence markers. Undifferentiated and differentiated ASC and MSC from animals of different ages expressed Notch-2 at similar levels; protein-38 and protein-53 were present in all groups of cells with a trend towards increased levels in cells from older animals compared to those from neonatal and young rats. Following co-culture with adult neuronal cells, dMSC and dASC from animals of all ages elicited robust neurite outgrowth. Mitotracker (R) staining was consistent with ultrastructural changes seen in the mitochondria of cells from old rats, indicative of senescence. In conclusion, this study showed that although the cells from aged animals expressed markers of senescence, aged MSC and ASC differentiated into SC-like cells still retain potential to support axon regeneration.

  • 242.
    Mantovani, Maria Cristina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Schwann cells and mesenchymal stem cells as promoter of peripheral nerve regeneration2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The transplantation of primary Schwann cells (SC) has been shown to improve nerve regeneration. However, to monitor the survival of transplanted cells within the host, a stable labelling method is required. The in vitro characteristics of green fluorescent protein labelled SC (GFP SC) and their effects in an in vivo peripheral nerve injury model were investigated.   The GFP-SC were readily visualised ex vivo and stimulated significantly better axonal regeneration compared to controls. Clinical use of autologous SC for the treatment of nerve injuries is of limited use due to difficulty in obtaining clinically useful numbers. However, bone marrow mesenchymal stem cells (MSC) can trans-differentiate into SC like cells (dMSC). The in vitro and in vivo differentiation of MSC was explored, and the study extended to include the easily-accessible adipose stem cells (ASC).  In vitro, glial growth factor stimulated MSC express S100, a SC marker, and its expression is maintained following in vivo transplantation.  Similarly, untreated MSC transplanted in vivo also expressed S100, which indicates glial differentiation in response to local cytokines and growth factors. Using an in vitro model, comprising dMSC or dASC co-cultured with adult dorsal root ganglia (DRG) neurons, the capacity of the dMSC and SC like differentiated ASC (dASC) to promote axon myelination was verified: both cell types expressed transcripts for protein zero, peripheral myelin protein-22 and myelin basic protein.

    The potential of stem cells in nerve repair may be limited by innate cellular senescence or donor age affecting cell functionality thus it was essential to determine the effects of donor age on morphology and functionality of stem cells.  The proliferation rates, expression of senescence markers (p38 and p53) and the stimulation of neurite outgrowth from DRG neurons by stem cells isolated from neonatal, young or old rats were very similar. However, the distribution and ultrastructure of mitochondria in dMSC and dASC from young and old rats were quite different, and seem to indicate physiological senescence of the aged cells.  Given the wide-ranging influence of Notch signalling in cell differentiation, including the neural crest to a glial cell type switch, and self-renewal in mammals, its role in the differentiation of stem cells to SC was investigated. The mRNA for notch-1 and -2 receptors were expressed in the dASC, blockage of notch signaling did not affect the neurotrophic and myelination potential of dASC. 

    In conclusion, these findings show that GFP labelling has no deleterious effect on SC survival and function. MSC and ASC differentiated into glial-type cells acquire SC morphology, and express characteristic SC markers, and the differentiation process was independent of the Notch signaling pathway. Also, following transplantation into a nerve gap injury dMSC improve regeneration. This study established that following co-culture with DRG neurons, dMSC and dASC were able to express peripheral myelin proteins.  Also, the functional bioactivity of these cells is independent of the donor animal age. Finally, although the glial lineage differentiated aged cells characterized in this study expressed markers typical of senescence they retained the potential to support axon regeneration.

  • 243. Masci, Lorenzo
    et al.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    van Schie, Hans T M
    Alfredson, Håkan
    Achilles tendinopathy - do plantaris tendon removal and Achilles tendon scraping improve tendon structure?: A prospective study using ultrasound tissue characterisation2015In: BMJ Open Sport & Exercise Medicine, ISSN 2055-7647, Vol. 1, no 1, article id e000005Article in journal (Refereed)
    Abstract [en]

    Objectives The plantaris tendon has recently been described as a possible important factor in midportion Achilles tendinopathy. Ultrasound tissue characterisation (UTC) is a method to study tendon structure (matrix integrity). The effect of plantaris tendon removal on Achilles tendon structure was studied using UTC.

    Design and setting Prospective case series study at one centre.

    Participants Nine tendons in eight physically active and healthy patients (mean age 39 years) with chronic painful midportion Achilles tendinopathy were included. Preoperative two-dimensional ultrasound and UTC showed midportion Achilles tendinopathy (tendinosis) with medial tendon changes and suspected plantaris tendon involvement. Patients with previous operations to the Achilles tendon were excluded.

    Interventions Operative treatment consisted of excision of the plantaris tendon and scraping of the ventromedial surface of the Achilles tendon under a local anaesthetic.

    Primary and secondary outcome measures UTC examination and clinical scoring with the VISA-A questionnaire were performed preoperatively and 6 months postoperatively.

    Results At 6 months follow-up, UTC demonstrated a statistically significant (t=5.40, p<0.001) increase in the mean organised matrix (echo-type I+II) and a decrease in the mean disorganised matrix (echo-type III+IV). Seven out of eight patients were satisfied, and the VISA-A score had increased significantly (p<0.001) from 56.8 (range 34–73) preoperatively to 93.3 (range 87–100) postoperatively.

    Conclusions Excision of the plantaris tendon and scraping of the ventromedial Achilles tendon in chronic midportion tendinopathy seem to have the potential to improve tendon structure and reduce tendon pain. Studies on a larger group of patients and with a longer follow-up period are needed.

  • 244. Masci, Lorenzo
    et al.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    van Schie, Hans T. M.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Pure Sports Medicine Clinic; ISEH, University College London Hospitals.
    How to diagnose plantaris tendon involvement in midportion Achilles tendinopathy: clinical and imaging findings2016In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, article id 97Article in journal (Refereed)
    Abstract [en]

    Background: The purpose of this investigation was to evaluate if clinical assessment, Ultrasound + Colour Doppler (US + CD) and Ultrasound Tissue Characterisation (UTC) can be useful in detecting plantaris tendon involvement in patients with midportion Achilles tendinopathy. Methods: Twenty-three tendons in 18 patients (14 men, mean age: 37 years and 4 women: 44 years) (5 patients with bilateral tendons) with midportion Achilles tendinopathy were surgically treated with a scraping procedure and plantaris tendon removal. For all tendons, clinical assessment, Ultrasound + Colour Doppler (US + CD) examination and Ultrasound Tissue Characterisation (UTC) were performed. Results: At surgery, all 23 cases had a plantaris tendon located close to the medial side of the Achilles tendon. There was vascularised fat tissue in the interface between the Achilles and plantaris tendons. Clinical assessment revealed localised medial activity-related pain in 20/23 tendons and focal medial tendon tenderness in 20/23 tendons. For US + CD, 20/23 tendons had a tendon-like structure interpreted to be the plantaris tendon and localised high blood flow in close relation to the medial side of the Achilles. For UTC, 19/23 tendons had disorganised (type 3 and 4) echopixels located only in the medial part of the Achilles tendon indicating possible plantaris tendon involvement. Conclusions: US + CD directly, and clinical assessment indirectly, can detect a close by located plantaris tendon in a high proportion of patients with midportion Achilles tendinopathy. UTC could complement US + CD and clinical assessment by demonstrating disorganised focal medial Achilles tendon structure indicative of possible plantaris involvement.

  • 245.
    McGrath, Aleksandra
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Development of biosynthetic conduits for peripheral nerve repair2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Peripheral nerve injuries are often associated with significant loss of nervous tissue leading to poor restoration of function following repair of injured nerves. Although the injury gap could be bridged by autologous nerve graft, the limited access to donor material and additional morbidity such as loss of sensation and scarring have prompted a search for biosynthetic nerve transplants.

    The present thesis investigates the effects of a synthetic matrix BD™ PuraMatrix™ peptide (BD)hydrogel, alginate/fibronectin gel and fibrin glue combined with cultured rat Schwann cells or human bone marrow derived mesenchymal stem cells (MSC) on neuronal regeneration and muscle recovery after peripheral nerve injury in adult rats.

    In a sciatic nerve injury model, after 3 weeks postoperatively, the regenerating axons grew significantly longer distances within the conduits filled with BD hydrogel if compared with the alginate/fibronectin gel. The addition of rat Schwann cells to the BD hydrogel drastically increased regeneration distance with axons crossing the injury gap and entering into the distal nerve stump. However, at 16 weeks the number of regenerating spinal motoneurons was decreased to 49% and 31% in the BD hydrogel and alginate/fibronectin groups respectively. The recovery of the gastrocnemius muscle was also inferior in both experimental groups if compared with the nerve graft. The addition of the cultured Schwann cells did not further improve the regeneration of motoneurons and muscle recovery.

    The growth-promoting effects of the tubular conduits prepared from fibrin glue were also studied following repair of short and long peripheral nerve gaps. Retrograde neuronal labeling demonstrated that fibrin glue conduit promoted regeneration of 60% of injured sensory neurons and 52% of motoneurons when compared with the autologous nerve graft. The total number of myelinated axons in the distal nerve stump in the fibrin conduit group reached 86% of the nerve graft control and the weight of gastrocnemius and soleus muscles recovered to 82% and 89%, respectively. When a fibrin conduit was used to bridge a 20 mm sciatic nerve gap, the weight of gastrocnemius muscle reached only 43% of the nerve graft control. The morphology of the muscle showed a more atrophic appearance and the mean area and diameter of fast type fibres were significantly worse than those of the corresponding 10 mm gap group. In contrast, both gap sizes treated with nerve graft showed similar fiber size.

    The combination of fibrin conduit with human MSC and daily injections of cyclosporine A enhanced the distance of regeneration by four fold and the area occupied by regenerating axons by three fold at 3 weeks after nerve injury and repair. In addition, the treatment also significantly reduced the ED1 macrophage reaction. At 12 weeks after nerve injury the treatment with cyclosporine A alone or cyclosporine A combined with hMSC induced recovery of the muscle weight and the size of fast type fibres to the control levels of the nerve graft group.

    In summary, these results show that a BD hydrogel supplemented with rat Schwann cells can support the initial phase of neuronal regeneration across the conduit. The data also demonstrate an advantage of tubular fibrin conduits combined with human MSC to promote axonal regeneration and muscle recovery after peripheral nerve injury.

  • 246.
    McGrath, Aleksandra
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Paul, Kingham
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Fibrin conduit supplemented with human mesenchymal stem cells supports regeneration after peripheral nerve injury   Manuscript (preprint) (Other academic)
    Abstract [en]

    To address the need for the development of bioengineered replacement of a nerve graft for treatment of peripheral nerve injuries a novel two component fibrin glue conduit was combined with human mesenchymal stem cells (hMSC) and immunosupressive treatment with cyclosporine. MSC possess the advantage of lower donor site morbidity and easier expandability in vitro compared with Schwann cells. The effects of hMSC on axonal regeneration in the conduit and reaction of activated macrophages was investigated using sciatic nerve injury model. The experiments were performed on 20 female Fischer rats (8-10 weeks old). A 10mm gap in the sciatic nerve was created and repaired either with fibrin glue conduit containing diluted fibrin matrix or fibrin glue conduit containing fibrin matrix with hMSC at concentration of 80x106 cells per ml. Cells were labeled with PKH26 prior to transplantation. The animals were allowed to survive for 3 weeks and some groups were treated with daily injections of cyclosporine. After 3 weeks the conduits were harvested and the distance of regeneration and area occupied by regenerating axons together with ED1 staining of activated macrophages was measured. hMSC survived in the conduit and enhanced axonal regeneration only when transplantation was combined with cyclosporine treatment. Moreover, cyclosporine significantly reduced the ED1 macrophage reaction.

  • 247.
    McGrath, Aleksandra M
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 516, no 2, p. 171-176Article in journal (Refereed)
    Abstract [en]

    To address the need for the development of bioengineered replacement of a nerve graft, a novel two component fibrin glue conduit was combined with human mesenchymal stem cells (MSC) and immunosupressive treatment with cyclosporine A. The effects of MSC on axonal regeneration in the conduit and reaction of activated macrophages were investigated using sciatic nerve injury model. A 10mm gap in the sciatic nerve of a rat was created and repaired either with fibrin glue conduit containing diluted fibrin matrix or fibrin glue conduit containing fibrin matrix with MSC at concentration of 80×10(6)cells/ml. Cells were labeled with PKH26 prior to transplantation. The animals received daily injections of cyclosporine A. After 3 weeks the distance of regeneration and area occupied by regenerating axons and ED1 positives macrophages was measured. MSC survived in the conduit and enhanced axonal regeneration only when transplantation was combined with cyclosporine A treatment. Moreover, addition of cyclosporine A to the conduits with transplanted MSC significantly reduced the ED1 macrophage reaction.

  • 248.
    McGrath, Aleksandra M.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Norrlands Univ Hosp, Sect Hand & Plast Surg, Dept Surg & Perioperat Sci, Umea, Sweden.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Norrlands Univ Hosp, Sect Hand & Plast Surg, Dept Surg & Perioperat Sci, Umea, Sweden.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Norrlands Univ Hosp, Sect Hand & Plast Surg, Dept Surg & Perioperat Sci, Umea, Sweden.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model2018In: Cell Medicine, ISSN 2155-1790, Vol. 10, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Introduction: Previously we showed that a fibrin glue conduit with human mesenchymal stem cells (hMSCs) and cyclosporine A (CsA) enhanced early nerve regeneration. In this study long term effects of this conduit are investigated. Methods: In a rat model, the sciatic nerve was repaired with fibrin conduit containing fibrin matrix, fibrin conduit containing fibrin matrix with CsA treatment and fibrin conduit containing fibrin matrix with hMSCs and CsA treatment, and also with nerve graft as control. Results: At 12 weeks 34% of motoneurons of the control group regenerated axons through the fibrin conduit. CsA treatment alone or with hMSCs resulted in axon regeneration of 67% and 64% motoneurons respectively. The gastrocnemius muscle weight was reduced in the conduit with fibrin matrix. The treatment with CsA or CsA with hMSCs induced recovery of the muscle weight and size of fast type fibers towards the levels of the nerve graft group. Discussion: The transplantation of hMSCs for peripheral nerve injury should be optimized to demonstrate their beneficial effects. The CsA may have its own effect on nerve regeneration.

  • 249.
    McGrath, Aleksandra M
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    BD™ PuraMatrix™ peptide hydrogel seeded with Schwann cells for peripheral nerve regeneration2010In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 83, no 5, p. 207-213Article in journal (Refereed)
    Abstract [en]

    This study investigated the effects of a membrane conduit filled with a synthetic matrix BD™ PuraMatrix™ peptide (BD) hydrogel and cultured Schwann cells on regeneration after peripheral nerve injury in adult rats. After sciatic axotomy, a 10mm gap between the nerve stumps was bridged using ultrafiltration membrane conduits filled with BD hydrogel or BD hydrogel containing Schwann cells. In control experiments, the nerve defect was bridged using either membrane conduits with alginate/fibronectin hydrogel or autologous nerve graft. Axonal regeneration within the conduit was assessed at 3 weeks and regeneration of spinal motoneurons and recovery of muscle weight evaluated at 16 weeks postoperatively. Schwann cells survived in the BD hydrogel both in culture and after transplantation into the nerve defect. Regenerating axons grew significantly longer distances within the conduits filled with BD hydrogel when compared with the alginate/fibronectin hydrogel and alginate/fibronectin with Schwann cells. Addition of Schwann cells to the BD hydrogel considerably increased regeneration distance with axons crossing the injury gap and entering into the distal nerve stump. The conduits with BD hydrogel showed a linear alignment of nerve fibers and Schwann cells. The number of regenerating motoneurons and recovery of the weight of the gastrocnemius muscle was inferior in BD hydrogel and alginate/fibronectin groups compared with nerve grafting. Addition of Schwann cells did not improve regeneration of motoneurons or muscle recovery. The present results suggest that BD hydrogel with Schwann cells could be used within biosynthetic conduits to increase the rate of axonal regeneration across a nerve defect.

  • 250.
    McKay Hart, Andrew
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Sensory neuronal protection & improving regeneration after peripheral nerve injury2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Peripheral nerve trauma is a common cause of considerable functional morbidity, and healthcare expenditure. Particularly in the ~15% of injuries unsuitable for primary repair, standard clinical management results in inadequate sensory restitution in the majority of cases, despite the rigorous application of complex microsurgical techniques. This can largely be explained by the failure of surgical management to adequately address the neurobiological hurdles to optimal regeneration. Most significant of these is the extensive sensory neuronal death that follows injury, and which is accompanied by a reduction in the regenerative potential of axotomised neurons, and in the supportive capacity of the Schwann cell population if nerve repair is delayed.

    The present study aimed to accurately delineate the timecourse of neuronal death, in order to identify a therapeutic window during which clinically applicable neuroprotective strategies might be adopted. It then proceeded to investigate means to increase the regenerative capacity of chronically axotomised neurons, and to augment the Schwann cells’ ability to promote that regenerative effort.

    Unilateral sciatic nerve transection in the rat was the model used, initially assessing neuronal death within the L4&5 dorsal root ganglia by a combination of morphology, TdT uptake nick-end labelling (TUNEL), and statistically unbiased estimation of neuronal loss using the stereological optical disector technique. Having identified 2 weeks, and 2 months post-axotomy as the most biologically relevant timepoints to study, the effect upon neuronal death of systemic treatment with acetyl-L-carnitine (ALCAR 10, or 50mg/kg/day) or N-acetyl-cysteine (NAC 30, or 150mg/kg/day) was determined. A model of secondary nerve repair was then adopted; either 2 or 4 months after unilateral sciatic nerve division, 1cm gap repairs were performed using either reversed isografts, or poly-3-hydroxybutyrate (PHB) conduits containing an alginate-fibronectin hydrogel. Six weeks later nerve regeneration and the Schwann cell population were quantified by digital image analysis of frozen section immunohistochemistry.

    Sensory neuronal death begins within 24 hours of injury, but takes 1 week to translate into significant neuronal loss. The rate of neuronal death peaks 2 weeks after injury, and neuronal loss is essentially complete by 2 months post-axotomy. Nerve repair is incompletely neuroprotective, but the earlier it is performed the greater the benefit. Two clinically safe pharmaceutical agents, ALCAR & NAC, were found to virtually eliminate sensory neuronal death after peripheral nerve transection. ALCAR also enhanced nerve regeneration independently of its neuroprotective role. Plain PHB conduits were found to be technically simple to use, and supported some regeneration, but were not adequate in themselves. Leukaemia inhibitory factor enhanced nerve regeneration, though cultured autologous Schwann cells (SC’s) were somewhat more effective. Both were relatively more efficacious after a 4 month delay in nerve repair. The most profuse regeneration was found with recombinant glial growth factor (rhGGF-2) in repairs performed 2 months after axotomy, with results that were arguably better than were obtained with nerve grafts. A similar conclusion can be drawn from the result found using both rhGGF-2 and SC’s in PHB conduits 4 months after axotomy.

    In summary, these findings reinforce the significance of sensory neuronal death in peripheral nerve trauma, and the possibility of its` limitation by early nerve repair. Two agents for the adjuvant therapy of such injuries were identified, that can virtually eliminate neuronal death, and enhance regeneration. Elements in the creation of a bioartificial nerve conduit to replace, or surpass autologous nerve graft for secondary nerve repair are presented.

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