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  • 51. Button, J.
    et al.
    Scott, J.
    Taghizadeh, R.
    Weiler-Mithoff, E.
    Hart, Andrew M.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK; Department of Surgical and Perioperative Science, Section for Hand & Plastic Surgery, University Hospital, Umea, Sweden.
    Shoulder function following autologous latissimus dorsi breast reconstruction: A prospective three year observational study comparing quilting and non-quilting donor site techniques2010Inngår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 63, nr 9, s. 1505-1512Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Latissimus dorsi harvest and axillary surgery can affect shoulder function. The effect of autologous latissimus dorsi flap (ALD) breast reconstruction and donor site quilting have been inadequately studied. A cohort of ALD flap breast reconstruction patients were assessed pre-operatively and at eight post-operative time-points (up to 3 years after reconstruction) using the self-administered Disabilities of the Arm, Shoulder and Hand (DASH) outcome measure, for which validated normative data is available. Patients with incidental shoulder conditions and bilateral reconstructions were excluded. This was a prospective, observational study with blinded data interpretation: 58 patients, 22 of whom had donor site quilting, were assessed. Groups were compatible demographically, in breast care management and in pre-operative DASH score (quilted 6.5, non-quilted 6.4; P = 0.98). Scores were significantly increased at initial post-operative clinic review (mean 49, SD19; P < 0.001), 6 week (29, SD20; P < 0.001), and 3 month (19, SD19; P < 0.01), thereafter remaining at a plateau value of similar to 15 (P > 0.05). Seroma incidence was reduced in the quilted group (5% vs 70%). A strong, significant correlation was found between 3 month DASH score and long term function (r = 0.66, P < 0.0003); patients with DASH > 20 fare significantly worse in the long-term (mean 20 point increase, SD5.0, P < 0.001). Higher post-operative DASH scores correlated significantly with pre-operative DASH (r = 0.58) and BMI (r = 0.36). Adjuvant therapy had no effect on shoulder function. Axillary dissection had a weak correlation with a higher DASH score, but only at the 3-month post-operative time-point (r = 0.32, P = 0.03). ALD flap breast reconstruction generally results in a functionally insignificant increase (6.5 points) in longterm DASH score, although a small subset of patients do develop longterm impairment, and quilting does not appear to inhibit shoulder function. (C) 2009 British Association of Plastic, Reconstructive and Aesthetic Surgeons.

  • 52.
    Byström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Carracedo, Sergio
    Behndig, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Gullberg, Donald
    Pedrosa-Domellöf, Fatima
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alpha11 integrin in the human cornea: importance in development and disease.2009Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 50, nr 11, s. 5044-5053Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To examine the distribution of the alpha11 integrin chain in the human cornea during fetal development and in normal and diseased adult human corneas.

    METHODS: Six fetal corneas, 10 to 20 weeks of gestation (wg), and 18 adult corneas including 3 normal, 7 with keratoconus, 5 with pseudophakic bullous keratopathy (PBK), 2 with Fuchs' corneal dystrophy, and 1 with a scar after deep lamellar keratoplasty (DLKP) were processed for immunohistochemistry with specific antibodies against the alpha11 integrin chain; collagen I, IV, and V; and alpha-smooth muscle actin (alpha-SMA). The cellular source of alpha11 integrin chain was further investigated in cell cultures.

    RESULTS: At 10 to 17 wg, the alpha11 integrin chain was predominantly present in the anterior corneal stroma. At 20 wg, in normal adult corneas and in Fuchs' dystrophy corneas there was weak staining in the stroma. The PBK corneas showed variable and weak staining, generally accentuated in the posterior stroma near Descemet's membrane. In contrast, the anterior portion of the stroma in the keratoconus corneas was strongly stained in an irregular streaky pattern. Human corneal fibroblasts/myofibroblasts produced alpha11 integrin chain in culture. Cultures treated with TGF-beta showed higher content of both alpha-SMA and the alpha11 integrin chain.

    CONCLUSIONS: The presence of the alpha11 integrin chain during early corneal development and the enhanced expression in scarred keratoconus corneas indicates that this integrin chain is likely to play an important role in collagen deposition during corneal development and in keratoconus with a scarring component and compromised basement membrane integrity.

  • 53.
    Byström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Virtanen, Ismo
    Rousselle, Patricia
    Gullberg, Donald
    Pedrosa-Domellöf, Fatima
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Distribution of laminins in the developing human eye2006Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 47, nr 3, s. 777-785Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To examine the distribution of laminin (Ln) chains in basement membranes (BMs) of the human cornea, lens, and retina in fetal development. METHODS: Ten fetal eyes (9-20 weeks of gestation [wg]) were serially sectioned and treated with specific antibodies against the Ln-alpha1, -alpha2, -alpha3, -alpha4, -alpha5, -beta1, -beta2, -beta3, and -gamma1 chains. RESULTS: The BM of the corneal epithelium was reactive for Ln-alpha3, -alpha5, -beta1, and beta3 chains through all ages, whereas the Ln-alpha1 chain was present at 9 to 12 wg and the Ln-alpha4 chain from 10 wg. The Descemet's membrane (DM) was labeled with the Ln-alpha1 and -alpha4 chains at 10 to 17 wg, the Ln-alpha5 chain from 10 wg, the Ln-beta1 chain at 11 to 17 wg, and the Ln-beta3 chain from 17 wg. The Ln-alpha1, alpha5, -beta1, and -beta2 chains were present in the lens capsule and the internal limiting membrane (ILM) through all ages. The Bruch's membrane (BrM) was immunoreactive for the Ln-alpha3, alpha4, -alpha5, -beta1, and -beta2 chains through all ages, whereas the Ln-alpha1 chain was absent from 20 wg onward. The Ln-alpha2 chain was not detected in the eye, but it was present in the extraocular muscles. CONCLUSIONS: BMs play an important role during morphogenesis, in that they influence cell proliferation, migration, and tissue differentiation. Lns are the major noncollagenous component of BMs. The presence of four different alpha chains, three beta chains, and one gamma chain of Ln in the eye reveals a high degree of complexity from the early stages of development and suggests an important role for the different Ln chains in human ocular differentiation.

  • 54. Caddick, Jenny
    et al.
    Kingham, Paul J
    Gardiner, Natalie J
    Wiberg, Mikael
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage.2006Inngår i: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 54, nr 8, s. 840-849Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have investigated the phenotypic and bioassay characteristics of bone marrow mesenchymal stromal cells (MSCs) differentiated along a Schwann cell lineage using glial growth factor. Expression of the Schwann cell markers S100, P75, and GFAP was determined by immunocytochemical staining and Western blotting. The levels of the stem cell markers Stro-1 and alkaline phosphatase and the neural progenitor marker nestin were also examined throughout the differentiation process. The phenotypic properties of cells differentiated at different passages were also compared. In addition to a phenotypic characterization, the functional ability of differentiated MSCs has been investigated employing a co-culture bioassay with dissociated primary sensory neurons. Following differentiation, MSCs underwent morphological changes similar to those of cultured Schwann cells and stained positively for all three Schwann cell markers. Quantitative Western blot analysis showed that the levels of S100 and P75 protein were significantly elevated upon differentiation. Differentiated MSCs were also found to enhance neurite outgrowth in co-culture with sensory neurons to a level equivalent or superior to that produced by Schwann cells. These findings support the assertion that MSCs can be differentiated into cells that are Schwann cell-like in terms of both phenotype and function.

  • 55.
    Carlsson, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The muscle cytoskeleton of mice and men: Structural remodelling in desmin myopathies2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The muscle fibre cytoskeleton of skeletal and heart muscle cells is composed mainly of intermediate filaments (IFs), that surround the myofibrils and connect the peripheral myofibrils with the sarcolemma and the nuclear membrane. Desmin is the first muscle specific IF protein to be produced in developing muscles and is the main IF protein in mature muscles. In skeletal muscle, desmin is particularly abundant at myotendinous and neuromuscular junctions. In the heart an increased amount of desmin is found at intercalated discs and in Purkinje fibres of the conduction system. Interactions between the IFs themselves, and between IFs and other structures such as Z-discs and the sarcolemma, are mediated by intermediate filament associated proteins (IFAPs). A transgenic mice model, which lacks the desmin gene have been developed to study the function of desmin. In these mice, morphological abnormalities are observed in both heart and skeletal muscles. Similar defects have been observed in human myopathies, caused by different mutations in the desmin gene. In the present thesis, skeletal and heart muscles of both wild type and desmin knock-out (K/O) mice have been investigated. Furthermore the cytoskeletal organisation in skeletal muscles from human controls and from a patient with desmin myopathy was examined.

    In the desmin K/O mice, no morphological alterations were observed during embryogenesis. These mice postnatally developed a cardiomyopathy and a muscle dystrophy in highly used skeletal muscles. Ruptures of the sarcolemma appear to be the primary event leading to muscle degeneration and fibrosis both in cardiac and affected skeletal muscles. In the heart the muscle degeneration gave rise to calcifications, whereas in skeletal muscles regeneration of affected muscle was seen.

    In mature wild type mice, the IF proteins synemin and paranemin, and the IFAP plectin were present together with desmin at the myofibrillar Z-discs, the sarcolemma, the neuromuscular junctions and the myotendinous junctions. Nestin was only found in these junctional regions. In desmin K/O mice, all four proteins were detected at neuromuscular and myotendinous junctions. The normal network of synemin and paranemin were not observed, whereas the distribution of plectin was preserved.

    In normal human muscles, synemin, paranemin, plectin and αB-crystallin were colocalised with desmin in between the myofibrils, at the sarcolemma and at myotendinous and neuromuscular junctions. In the human desmin myopathy, the distribution of desmin varied considerably. A normal pattern was seen in some fibres areas, whereas other regions either contained large subsarcolemmal and intermyofibrillar accumulations of desmin or totally lacked desmin. Nestin, synemin, paranemin, plectin and αB-crystallin also exhibited an abnormal distribution. They were often aggregated in the areas that contained accumulations of desmin.

    In cultured satellite cells from the patient, a normal network of desmin was present in early passages, whereas aggragates of desmin occurred upon further culturing. In the latter, also the nestin network was disrupted, whereas vimentin showed a normal pattern. αB-crystallin was only present in cells with a disrupted desmin network. Plectin was present in a subset of cells, irrespective of whether desmin was aggregated or showed a normal network.

    From the present study it can be concluded that an intact desmin network is needed to maintain the integrity of muscle fibres. Desmin may be an important component in the assembly of proteins, which connect the extrasarcomeric cytoskeleton with the extracellular matrix.

  • 56.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Fischer, Christine
    Karoloinska Institute.
    Sjöberg, Gunnnar
    Karoloinska Institute.
    Robson, Richard M
    Iowa Statte University.
    Sejersen, Thomas
    Karoloinska Institute.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Cytoskeletal derangements in hereditary myopathy with a desmin L345P mutation2002Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, nr 5, s. 493-504Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with abnormal accumulations of desmin have been described in myopathies with or without cardiac involvement. Desmin deposits were sometimes associated with abnormal aggregates of other cytoskeletal proteins. In the present study we present how the cytoskeletal organisation of desmin, nestin, synemin, paranemin, plectin and alphaB-crystallin is altered in skeletal muscles from a patient with a L345P mutation in the desmin gene. In general, accumulations of desmin together with synemin, nestin, plectin and alphaB-crystallin were present between myofibrils and beneath the sarcolemma. However, as the biopsy samples were very myopathic, large variability in fibre size and fibre maturation was seen, thus the myofibrillar content and the cytoskeletal organisation varied considerably. In cultured satellite cells from the patient, desmin aggregates were not observed in initial passages, but occurred over time in culture in the form of perinuclear, peripheral or cytoplasmic deposits. Nestin colocalised to the abnormal desmin deposits to a larger extent than did vimentin. alphaB-Crystallin was only present in cells with a disrupted desmin network. Plectin was altered in a subset of cells with a disrupted desmin network, whereas synemin and paranemin were not detected. We conclude that the L345P desmin mutation has a profound influence on the cytoskeletal organisation both in vivo and in vitro, which reflects the pathogenesis of the desmin myopathy.

  • 57.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Li, Z L
    Université Paris.
    Paulin, D
    Université Paris.
    Price, M G
    Baylor College of Medicine.
    Breckler, J
    San Fransisco State University.
    Robson, R M
    Iowa State University.
    Wiche, G
    University of Vienna.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Differences in the distribution of synemin, paranemin, and plectin in skeletal muscles of wild-type and desmin knock-out mice2000Inngår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 114, nr 1, s. 39-47Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mice lacking the gene encoding for the intermediate filament protein desmin have a surprisingly normal myofibrillar organization in skeletal muscle fibers, although myopathy develops in highly used muscles. In the present study we examined how synemin, paranemin, and plectin, three key cytoskeletal proteins related to desmin, are organized in normal and desmin knock-out (K/O) mice. We show that in wild-type mice, synemin, paranemin, and plectin were colocalized with desmin in Z-disc-associated striations and at the sarcolemma. All three proteins were also present at the myotendinous junctions and in the postsynaptic area of motor endplates. In the desmin K/O mice the distribution of plectin was unaffected, whereas synemin and paranemin were partly affected. The Z-disc-associated striations were in general no longer present in between the myofibrils. In contrast, at the myotendinous and neuromuscular junctions synemin and paranemin were still present. Our study shows that plectin differs from synemin and paranemin in its binding properties to the myofibrillar Z-discs and that the cytoskeleton in junctional areas is particularly complex in its organization.

  • 58.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Desmin-related myopathies in mice and man2001Inngår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 171, nr 3, s. 341-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Desmin, the main intermediate filament (IF) protein in skeletal and heart muscle cells, is of great importance as a part of the cytoskeleton. The IFs surround and interlink myofibrils, and connect the peripheral myofibrils with the sarcolemma. In myotendinous junctions and neuromuscular junctions of skeletal muscle fibres, desmin is enriched. In the heart, desmin is increased at intercalated discs, the attachment between cardiomyocytes, and it is the main component in Purkinje fibres of the conduction system. Desmin is the first muscle-specific protein to appear during myogenesis. Nevertheless, lack of desmin, as shown from experiments with desmin knockout (K/O) mice, does not influence myogenesis or myofibrillogenesis. However, the desmin knock-out mice postnatally develop a cardiomyopathy and a muscle dystrophy in highly used skeletal muscles. In other skeletal muscles the organization of myofibrils is remarkably unaffected. Thus, the main consequence of the lack of desmin is that the muscle fibres become more susceptible to damage. The loss of membrane integrity leads to a dystrophic process, with degeneration and fibrosis. In the heart cardiac failure develops, whereas in affected skeletal muscles regenerative attempts are seen. In humans, accumulations of desmin have been a hallmark for presumptive desmin myopathies. Recent investigations have shown that some families with such a myopathy have a defect in the gene coding for alphaB-crystallin, whereas others have mutations in the desmin gene. Typical features of these patients are cardiac affections and muscle weakness. Thus, mutations in the desmin gene is pathogenic for a distinct type of muscle disorder.

  • 59.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Yu, Ji-Guo
    Department of Natural and Environmental Physiology, Mid Sweden University.
    Moza, Monica
    Department of Pathology and Neuroscience Program, Biomedicum Helsinki, University of Helsinki and University Central Hospital, Finland.
    Carpén, Olli
    Department of Pathology, University of Turku and Turku University Central Hospital, Finland.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Myotilin: a prominent marker of myofibrillar remodelling2007Inngår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 17, nr 1, s. 61-68Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myofibrillar remodelling with insertion of sarcomeres is a typical feature of biopsies taken from persons suffering of exercise-induced delayed onset muscle soreness. Here we studied the presence of the sarcomeric protein myotilin in eccentric exercise related lesions. Myotilin is a component of sarcomeric Z-discs and it binds several other Z-disc proteins, i.e. alpha-actinin, filamin C, F-actin and FATZ. Myotilin has previously been shown to be present in nemaline rods and central cores and to be mutated in limb girdle muscular dystrophy 1A (LGMD1A) and in a subset of myofibrillar myopathies, indicating an important role in Z-disc maintenance. Our findings on non-diseased muscle affected by eccentric exercise give new information on how myotilin is associated to myofibrillar components upon remodelling. We show that myotilin was present in increased amount in lesions related to Z-disc streaming and events leading to insertion of new sarcomeres in pre-existing myofibrils and can therefore be used as a marker for myofibrillar remodelling. Interestingly, myotilin is preferentially associated with F-actin rather than with the core Z-disc protein alpha-actinin during these events. This suggests that myotilin has a key role in the dynamic molecular events mediating myofibrillar assembly in normal and diseased skeletal muscle.

  • 60.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Yu, Ji-Guo
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    New aspects of obscurin in human striated muscles.2008Inngår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 130, nr 1, s. 91-103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obscurin is a giant protein (700-800 kDa) present in both skeletal muscles and myocardium. According to animal studies, obscurin interacts with myofibrillar Z-discs during early muscle development, but is translocalised to be predominantly associated with the M-bands in mature muscles. The proposed function for obscurin is in the assembly and organisation of myosin into regular A-bands during formation of new sarcomeres. In the present study, the precise localisation of obscurin in developing and mature normal human striated muscle is presented for the first time. We show that obscurin surrounded myofibrils at the M-band level in both developing and mature human skeletal and heart muscles, which is partly at variance with that observed in animals. At maturity, obscurin also formed links between the peripheral myofibrils and the sarcolemma, and was a distinct component of the neuromuscular junctions. Obscurin should therefore be regarded as an additional component of the extrasarcomeric cytoskeleton. To test this function of obscurin, biopsies from subjects with exercise-induced delayed onset muscle soreness (DOMS) were examined. In these subjects, myofibrillar alterations related to sarcomerogenesis are observed. Our immunohistochemical analysis revealed that obscurin was never lacking in myofibrillar alterations, but was either preserved at the M-band level or diffusely spread over the sarcomeres. As myosin was absent in such areas but later reincorporated in the newly formed sarcomeres, our results support that obscurin also might play an important role in the formation and maintenance of A-bands.

  • 61.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Chen, Peng
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhou, Qingjun
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Ciliary Neurotrophic Factor Promotes the Migration of Corneal Epithelial Stem/progenitor Cells by Up-regulation of MMPs through the Phosphorylation of Akt2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 25870Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The migration of limbal epithelial stem cells is important for the homeostasis and regeneration of corneal epithelium. Ciliary neurotrophic factor (CNTF) has been found to promote corneal epithelial wound healing by activating corneal epithelial stem/progenitor cells. However, the possible effect of CNTF on the migration of corneal epithelial stem/progenitor cells is not clear. This study found the expression of CNTF in mouse corneal epithelial stem/progenitor cells (TKE2) to be up-regulated after injury, on both gene and protein level. CNTF promoted migration of TKE2 in a dose-dependent manner and the peak was seen at 10 ng/ml. The phosphorylation level of Akt (p-Akt), and the expression of MMP3 and MMP14, were up-regulated after CNTF treatment both in vitro and in vivo. Akt and MMP3 inhibitor treatment delayed the migration effect by CNTF. Finally, a decreased expression of MMP3 and MMP14 was observed when Akt inhibitor was applied both in vitro and in vivo. This study provides new insights into the role of CNTF on the migration of corneal epithelial stem/progenitor cells and its inherent mechanism of Up-regulation of matrix metalloproteinases through the Akt signalling pathway.

  • 62.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Lan, Jie
    Liu, Dongle
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhang, Wei
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhou, Qingjun
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Ascorbic Acid Promotes the Stemness of Corneal Epithelial Stem/Progenitor Cells and Accelerates Epithelial Wound Healing in the Cornea2017Inngår i: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 6, nr 5, s. 1356-1365Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High concentration of ascorbic acid (vitamin C) has been found in corneal epithelium of various species. However, the specific functions and mechanisms of ascorbic acid in the repair of corneal epithelium are not clear. In this study, it was found that ascorbic acid accelerates corneal epithelial wound healing in vivo in mouse. In addition, ascorbic acid enhanced the stemness of cultured mouse corneal epithelial stem/progenitor cells (TKE2) in vitro, as shown by elevated clone formation ability and increased expression of stemness markers (especially p63 and SOX2). The contribution of ascorbic acid on the stemness enhancement was not dependent on the promotion of Akt phosphorylation, as concluded by using Akt inhibitor, nor was the stemness found to be dependent on the regulation of oxidative stress, as seen by the use of two other antioxidants (GMEE and NAC). However, ascorbic acid was found to promote extracellular matrix (ECM) production, and by using two collagen synthesis inhibitors (AzC and CIS), the increased expression of p63 and SOX2 by ascorbic acid was decreased by around 50%, showing that the increased stemness by ascorbic acid can be attributed to its regulation of ECM components. Moreover, the expression of p63 and SOX2 was elevated when TKE2 cells were cultured on collagen I coated plates, a situation that mimics the in vivo situation as collagen I is the main component in the corneal stroma. This study shows direct therapeutic benefits of ascorbic acid on corneal epithelial wound healing and provides new insights into the mechanisms involved.

  • 63.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, Zhejiang; Zhejiang Provincial Key Lab forTissue Engineering and Regenerative Medicine, Hangzhou, Zhejiang, People’s Republic of China.
    Zhang, Erchen
    Zhang, Wei
    Liu, Zeyu
    Lu, Ping
    Zhu, Ting
    Yin, Zi
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Liu, Huanhuan
    Chen, Xiao
    Ouyang, Hongwei
    Fos Promotes Early Stage Teno-Lineage Differentiation of Tendon Stem/Progenitor Cells in Tendon2017Inngår i: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 6, nr 11, s. 2009-2019Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stem cells have been widely used in tendon tissue engineering. The lack of refined and controlled differentiation strategy hampers the tendon repair and regeneration. This study aimed to find new effective differentiation factors for stepwise tenogenic differentiation. By microarray screening, the transcript factor Fos was found to be expressed in significantly higher amounts in postnatal Achilles tendon tissue derived from 1 day as compared with 7-days-old rats. It was further confirmed that expression of Fos decreased with time in postnatal rat Achilles tendon, which was accompanied with the decreased expression of multiply tendon markers. The expression of Fos also declined during regular in vitro cell culture, which corresponded to the loss of tendon phenotype. In a cell-sheet and a three-dimensional cell culture model, the expression of Fos was upregulated as compared with in regular cell culture, together with the recovery of tendon phenotype. In addition, significant higher expression of tendon markers was found in Fos-overexpressed tendon stem/progenitor cells (TSPCs), and Fos knock-down gave opposite results. In situ rat tendon repair experiments found more normal tendon-like tissue formed and higher tendon markers expression at 4 weeks postimplantation of Fos-overexpressed TSPCs derived nonscaffold engineering tendon (cell-sheet), as compared with the control group. This study identifies Fos as a new marker and functional driver in the early stage teno-lineage differentiation of tendon, which paves the way for effective stepwise tendon differentiation and future tendon regeneration.

  • 64.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhang, Wei
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Substance P and patterned silk biomaterial stimulate periodontal ligament stem cells to form corneal stroma in a bioengineered three-dimensional model2017Inngår i: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 8, artikkel-id 260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We aimed to generate a bioengineered multi-lamellar human corneal stroma tissue in vitro by differentiating periodontal ligament stem cells (PDLSCs) towards keratocytes on an aligned silk membrane.

    Methods: Human PDLSCs were isolated and identified. The neuropeptide substance P (SP) was added in keratocyte differentiation medium (KDM) to evaluate its effect on keratocyte differentiation of PDLSCs. PDLSCs were then seeded on patterned silk membrane and cultured with KDM and SP. Cell alignment was evaluated and the expression of extracellular matrix (ECM) components of corneal stroma was detected. Finally, multi-lamellar tissue was constructed in vitro by PDLSCs seeded on patterned silk membranes, which were stacked orthogonally and stimulated by KDM supplemented with SP for 18 days. Sections were prepared and subsequently stained with hematoxylin and eosin or antibodies for immunofluorescence observation of human corneal stroma-related proteins.

    Results: SP promoted the expression of corneal stroma-related collagens (collagen types I, III, V, and VI) during the differentiation induced by KDM. Patterned silk membrane guided cell alignment of PDLSCs, and important ECM components of the corneal stroma were shown to be deposited by the cells. The constructed multi-lamellar tissue was found to support cells growing between every two layers and expressing the main type of collagens (collagen types I and V) and proteoglycans (lumican and keratocan) of normal human corneal stroma.

    Conclusions: Multi-lamellar human corneal stroma-like tissue can be constructed successfully in vitro by PDLSCs seeded on orthogonally aligned, multi-layered silk membranes with SP supplementation, which shows potential for future corneal tissue engineering.

  • 65.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhang, Wei
    Liu, Zeyu
    Zhu, Ting
    Shen, Weiliang
    Ran, Jisheng
    Tang, Qiaomei
    Gong, Xiaonan
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Chen, Xiao
    Chen, Xiaowen
    Wen, Feiqiu
    Ouyang, Hongwei
    Characterization and comparison of post-natal rat Achilles tendon-derived stem cells at different development stages2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 22946Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tendon stem/progenitor cells (TSPCs) are a potential cell source for tendon tissue engineering. The striking morphological and structural changes of tendon tissue during development indicate the complexity of TSPCs at different stages. This study aims to characterize and compare post-natal rat Achilles tendon tissue and TSPCs at different stages of development. The tendon tissue showed distinct differences during development: the tissue structure became denser and more regular, the nuclei became spindle-shaped and the cell number decreased with time. TSPCs derived from 7 day Achilles tendon tissue showed the highest self-renewal ability, cell proliferation, and differentiation potential towards mesenchymal lineage, compared to TSPCs derived from 1 day and 56 day tissue. Microarray data showed up-regulation of several groups of genes in TSPCs derived from 7 day Achilles tendon tissue, which may account for the unique cell characteristics during this specific stage of development. Our results indicate that TSPCs derived from 7 day Achilles tendon tissue is a superior cell source as compared to TSPCs derived from 1 day and 56 day tissue, demonstrating the importance of choosing a suitable stem cell source for effective tendon tissue engineering and regeneration.

  • 66.
    Ching, Rosanna C.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Schwann cell-like differentiated adipose stem cells promote neurite outgrowth via secreted exosomes and RNA transfer2018Inngår i: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 9, artikkel-id 266Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Adipose derived stem cells can be stimulated to produce a growth factor rich secretome which enhances axon regeneration. In this study we investigated the importance of exosomes, extracellular vesicles released by many different cell types, including stem cells and endogenous nervous system Schwann cells (SCs), on neurite outgrowth.

    Methods: Adipose derived stem cells were differentiated towards a Schwann cell-like phenotype (dADSCs) by in vitro stimulation with a mix of factors (basic fibroblast growth factor, platelet derived growth factor-AA, neuregulin-1 and forskolin). Using a precipitation and low-speed centrifugation protocol the extracellular vesicles were isolated from the medium of the stem cells cultures and also from primary SCs. The conditioned media or concentrated vesicles were applied to neurons in vitro and computerised image analysis was used to assess neurite outgrowth. Total RNA was purified from the extracellular vesicles and investigated using qRT-PCR.

    Results: Application of exosomes derived from SCs significantly enhanced in vitro neurite outgrowth and this was replicated by the exosomes from dADSCs. qRT-PCR demonstrated that the exosomes contained mRNAs and miRNAs known to play a role in nerve regeneration and these molecules were up-regulated by the Schwann cell differentiation protocol. Transfer of fluorescently tagged exosomal RNA to neurons was detected and destruction of the RNA by UV-irradiation significantly reduced the dADSCs exosome effects on neurite outgrowth. In contrast, this process had no significant effect on the SCs-derived exosomes.

    Conclusions: In summary, this work suggests that stem cell-derived exosomes might be a useful adjunct to other novel therapeutic interventions in nerve repair.

  • 67.
    Christensen, Jens
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin. UCLH, ISEH, London, England; Pure Sports Clin, London, England.
    Andersson, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Protease-activated receptors in the Achilles tendon-a potential explanation for the excessive pain signalling in tendinopathy2015Inngår i: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 11, artikkel-id 13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/Aim: Tendinopathies are pathological conditions of tissue remodelling occurring in the major tendons of the body, accompanied by excessive nociceptive signalling. Tendinopathies have been shown to exhibit an increase in the number of mast cells, which are capable of releasing histamine, tryptase and other substances upon activation, which may play a role in the development of tendinopathies. This study set out to describe the distribution patterns of a family of receptors called protease-activated receptors (PARs) within the Achilles tendon. These four receptors (PAR1, PAR2, PAR3, PAR4) are activated by proteases, including tryptase released from mast cells, and are involved in fibrosis, hyperalgesia and neovascularisation, which are changes seen in tendinopathies. Method: In order to study which structures involved in tendinopathy that these proteases can affect, biopsies from patients suffering of mid-portion Achilles tendinosis and healthy controls were collected and examined using immunohistochemistry. Tendon cells were cultured to study in vitro expression patterns. Results: The findings showed a distribution of PARs inside the tendon tissue proper, and in the paratendinous tissue, with all four being expressed on nerves and vascular structures. Double staining showed co-localisation of PARs with nociceptive fibres expressing substance P. Concerning tenocytes, PAR2, PAR3, and PAR4, were found in both biopsies of tendon tissue and cultured tendon cells. Conclusions: This study describes the expression patterns of PARs in the mid-portion of the Achilles tendon, which can help explain the tissue changes and increased pain signalling seen in tendinopathies. These findings also show that in-vitro studies of the effects of these receptors are plausible and that PARs are a possible therapeutic target in the future treatment strategies of tendinopathy.

  • 68. Cotrufo, Stefano
    et al.
    Dabernig, Joerg
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, University Hospital, Umea, Sweden.
    Vascular supply of the tensor fasciae latae flap revised2009Inngår i: Plastic and reconstructive surgery (1963), ISSN 0032-1052, E-ISSN 1529-4242, Vol. 123, nr 4, s. 161e-162eArtikkel i tidsskrift (Annet vitenskapelig)
  • 69.
    Cotrufo, Stefano
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; .
    Dabernig, Joerg
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Laboratory of Human Anatomy, University of Glasgow, Glasgow, United Kingdom.
    Russell, David
    Laboratory of Human Anatomy, University of Glasgow, Glasgow, United Kingdom.
    Payne, Anthony
    Laboratory of Human Anatomy, University of Glasgow, Glasgow, United Kingdom.
    Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; .
    The Vascular Anatomy of the Rat Superficial Epigastric Flap by Vascular Corrosion Casting and Technical Refinement for the Study of Choke Vessels in Cadaveric Flap Models2010Inngår i: Annals of Plastic Surgery, ISSN 0148-7043, E-ISSN 1536-3708, Vol. 64, nr 1, s. 93-97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Accurate depiction of cutaneous vascular microanatomy is of relevance to plastic surgical flap research, and to descriptive anatomy. Yet current techniques have not permitted full visualization of the subdermal plexus, or potential angiosomal connections. Nor has endothelial visualization been facilitated. Vascular corrosion casting techniques are promising in that regard, and were applied in an extended lateral thoracoabdominal suprafascial adipocutancous flap in the rat (based on the superficial epigastric bundle). Technical refinements for application to further study of human cadaveric flap models are presented. The intraflap vascular branching pattern of the superficial epigastric artery is described, with filling of the lateral thoracic, intercostals, and iliolumbar angiosomes found when coagulation of vessels at the periphery was delayed until after clearance. The vascular casting protocol presented is an effective and promising tool for the study of macro- and microvascular anatomy.

  • 70.
    Dabernig, Jörg
    et al.
    Glasgow Royal Infirmary.
    Ong, Keh O
    Glasgow Royal Infirmary.
    McGowan, Robert
    Glasgow Royal Infirmary.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Payne, Anthony P
    University of Glasgow.
    Hart, Andrew M
    Glasgow Royal Infirmary.
    The anatomic and radiologic basis of the circumflex scapular artery perforator flap2010Inngår i: Annals of Plastic Surgery, ISSN 0148-7043, E-ISSN 1536-3708, Vol. 64, nr 6, s. 784-788Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Microsurgical development has recently focused upon the perforator paradigm and primary thinning. Existing perforator flaps may require intramuscular dissection or lack reliable surface markings, whereas traditional scapular/parascapular flaps have low donor morbidity and reliable anatomy, but can be excessively bulky. Clinical application of a new flap based on a perforator from the circumflex scapular axis (CSA) has recently been published, but the vessel's anatomy has not been adequately characterized. The CSA was dissected in 115 sites in 69 cadavers. The number, external vessel diameter, and site of origin of perforators were measured relative to the CSA bifurcation. Color Doppler ultrasound was used to delineate the CSA and its perforators bilaterally in 40 volunteers. The number, origin relative to CSA bifurcation, diameter, length, and flow velocity of cutaneous perforators were determined. A CSA perforator was always present, running into the subdermal plexus, arising within 2.4 cm of the bifurcation. Cadaver studies: mean perforator diameter, 1.3 mm (SD, 0.66); 13% arose at bifurcation, 36% arose proximal (mean, 1.1 mm; SD, 0.63), and 52% distal to bifurcation (mean, 1.5 mm; SD, 0.88). Ultrasound: mean perforator diameter, 1.18 mm (SD, 0.41); mean flow velocity, 16.3 cm/s (SD, 3.65); perforator arose in 36% proximal, in 40% distal to bifurcation, and in 24% from the bifurcation. We definitively describe the anatomy of the perforator from the circumflex scapular artery upon which a new flap has been based. Its origin and dimensions are anatomically and radiologically reliable. The flap has certain potential benefits over existing perforator flaps.

  • 71.
    Dabernig, Jörg
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Sorensen, K
    Shaw-Dunn, J
    Hart, Andrew McKay
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    The thin circumflex scapular artery perforator flap2007Inngår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 60, nr 10, s. 1082-1096Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of microsurgery has most recently been focused upon the evolution of perforator flaps, with the aim of minimising donor site morbidity, and avoiding the transfer of functionally unnecessary tissues. The vascular basis of perforator flaps also facilitates radical primary thinning prior to flap transfer, when appropriate. Based upon initial clinical observations, cadaveric, and radiological studies, we describe a new, thin, perforator flap based upon the circumflex scapular artery (CSA). A perforator vessel was found to arise within 1.5cm of the CSA bifurcation (arising from the main trunk, or the descending branch). The perforator arborises into the sub-dermal vascular plexus of the dorsal scapular skin, permitting the elevation and primary thinning of a skin flap. This thin flap has been employed in a series of five clinical cases to reconstruct defects of the axilla (two cases of hidradenitis suppurativa; pedicled transfers), and upper limb (one sarcoma, one brachial to radial artery flowthrough revascularisation plus antecubital fossa reconstruction, and one hand reconstruction with a chimeric flap incorporating vascularised bone, fascia, and thin skin flaps; free tissue transfers). No intramuscular perforator dissection is required; pedicle length is 8-10cm and vessel diameter 2-4mm. There was no significant peri-operative complication or flap failure, all donor sites were closed primarily, patient satisfaction was high, and initial reconstructive aims were achieved in all cases. Surgical technique, and the vascular basis of the flap are described. The thin circumflex scapular artery perforator flap requires no intramuscular dissection yet provides high quality skin (whose characteristics can be varied by orientation of the skin paddle), and multiple chimeric options. The donor site is relatively hair-free, has favourable cosmesis and no known functional morbidity. This flap represents a promising addition to the existing range of perforator flaps.

  • 72.
    Dahl, Morten
    et al.
    Institute of Sports Medicine, Department 8, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Hansen, Philip
    Institute of Sports Medicine, Department 8, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Stål, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Edmundsson, David
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Magnusson, S. Peter
    Institute of Sports Medicine, Department 8, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Stiffness and thickness of Fascia do not explain chronic exertional compartment syndrome2011Inngår i: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 469, nr 12, s. 3495-3500Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background   Chronic exertional compartment syndrome is diagnosed based on symptoms and elevated intramuscular pressure and often is treated with fasciotomy. However, what contributes to the increased intramuscular pressure remains unknown.

    Questions/purposes   We investigated whether the stiffness or thickness of the muscle fascia could help explain the raised intramuscular pressure and thus the associated chronic compartment syndrome symptoms.

    Patients and Methods   We performed plain radiography, bone scan, and intramuscular pressure measurement to diagnose chronic compartment syndrome and to exclude other disorders. Anterior tibialis muscle fascial biopsy specimens from six healthy individuals, 11 patients with chronic compartment syndrome, and 10 patients with diabetes mellitus and chronic compartment syndrome were obtained. Weight-normalized fascial stiffness was assessed mechanically in a microtensile machine, and fascial thickness was analyzed microscopically.

    Results   Mean fascial stiffness did not differ between healthy individuals (0.120 N/mg/mm; SD, 0.77 N/mg/mm), patients with chronic compartment syndrome (0.070 N/mg/mm; SD, 0.052 N/mg/mm), and patients with chronic compartment syndrome and diabetes (0.097 N/mg/mm; SD, 0.073 N/mg/mm). Similarly, no differences in fascial thickness were present. There was a negative correlation between fascial stiffness and intramuscular pressure in the patients with chronic compartment syndrome and diabetes.

    Conclusions   The lack of difference in fascial thickness and stiffness in patients with chronic compartment syndrome and patients with chronic compartment syndrome and diabetes compared with healthy individuals suggests structural and mechanical properties are unlikely to explain chronic compartment syndrome. To prevent chronic exertional compartment syndrome, it is necessary to address aspects other than the muscle fascia.

  • 73.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Reviving the "biochemical" hypothesis for tendinopathy: new findings suggest the involvement of locally produced signal substances2009Inngår i: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 43, nr 4, s. 265-268Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies of recent years on human tendinopathies have provided us with evidence of a local, non-neuronal production in tendon cells (tenocytes) of signal substances traditionally confined to neurons. These substances include acetylcholine, catecholamines, substance P, and glutamate. Furthermore, the receptors for several of these substances have been found on nerve fascicles and in blood vessel walls, as well as on the tenocytes themselves, of the tendon tissue. The findings provide the basis for locally produced signal substances to influence pain signaling, vascular regulation, and/or tissue changes in tendinopathy. This reinforces a previously presented "biochemical" hypothesis for tendinopathy, suggesting that biochemical mediators in the tendon tissue might influence/irritate nociceptors, in or around the tendon, to cause chronic tendon pain. The potential clinical implications of the studies are considerable.

  • 74.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    What are the nerve related changes in tendinopathies and their implications for the cause and/or treatment of pain?2007Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Three theoretical models for possible nerve-related changes that occur in tendinopathies, either as cause or effects of the condition, are suggested: 1) changes in innervation patterns, 2) changes in nerve signaling/responsiveness, and 3) changes in production of (non-neuronal) signal substances. The scientific literature on the subject is reviewed, and studies in support of all three theories are presented. The conclusions are as follows: Changes in innervation patterns in tendinopathies are not fully verified, and not sufficient to explain the pain that occurs in tendinopathy. Changes in nerve sensitization/responsiveness cannot be ruled out, since there is a clear morphological basis in the form of several types of receptors demonstrated on nerves in tendons. Finally, there is novel evidence in favor of a biochemical explanation model, including a local, non-neuronal, production of signal substances, and also findings of receptors for these substances on nerves (and tenocytes). In summary, many possible sites for intervention in treatment of tendinopathy are suggested.

  • 75.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Är "nervsignalsubstanser utan nerver" svaret på tendinopatins gåta?: Om en muskelsenas förvandling vid kroniska smärttillstånd2009Inngår i: Svensk Idrottsforskning: Organ för Centrum för Idrottsforskning, ISSN 1103-4629, Vol. 18, nr 1, s. 50-52Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Forskare har i många år gäckats av frågan om vad som är orsaken till smärtan och vävnadsförändringarna vid kroniska senbesvär, s.k. tendinopati eller tendinos. Många teorier har framlagts, men få har kunnat bekräftas med forskningsresultat. I en aktuell serie studier från Umeå universitet, delvis i samarbete med kanadensiska forskare, har oväntade fynd kastat nytt ljus över gåtan. Helt överraskande har det visat sig att de sjuka muskelsenornas egna celler, de s.k. tenocyterna, producerar signalämnen som normalt bildas i nerver b ämnen som kan ha betydelse både för vävnadsnedbrytning och smärta

  • 76.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Distribution of general (PGP 9.5) and sensory (substance P/CGRP) innervations in the human patellar tendon.2006Inngår i: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 14, nr 2, s. 125-132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is no information on the pattern of blood vessel innervation, and in principle no information on innervation in general, in the human patellar tendon. In the present study, biopsies from the proximal part of normal and pain-free patellar tendons (11 men, mean age 33 years) were examined. The specimens were evaluated by using antibodies against the general nerve marker protein gene-product 9.5 (PGP 9.5) and the sensory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), and immunohistochemistry. It was observed that the arteries, and to some extent the small vessels, in the loose paratendinous connective tissue were supplied with PGP 9.5- as well as SP- and CGRP-innervations. There was a marked PGP 9.5-like immunoreaction (LI), and to some extent also SP- and CGRP-LI, in the large nerve fascicles in this tissue. In the tendon tissue proper, PGP 9.5-LI was detected in nerve fibers located in the vicinity of some of the blood vessels and in thin nerve fascicles. There was a low degree of SP- and CGRP-innervation in the tendon tissue proper. The observations give a morphologic correlate for the occurrence of nerve-mediated effects in the patellar tendon. Particularly it seems as if there is a marked nerve-mediated regulation of the blood vessels supplying the tendon, at the level where they course in the loose paratendinous connective tissue.

  • 77.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Extensive expression of markers for acetylcholine synthesis and of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendonosis - a case study2006Konferansepaper (Fagfellevurdert)
    Abstract [en]

    We have recently, in a study of a group of patients with chronic painful patellar tendon tendinosis (“jumper’s knee”), obtained evidence favoring the occurrence of an upregulation of a non-neuronal cholinergic system in this condition. Today, there is a new line of treatment of patellar tendinosis in the form of doppler guided sclerosing injections (Polidokanol), a treatment that has turned out to be very successful. However, the mechanisms for this therapy remain somewhat unclear. After an average of three treatments, a majority of the patients experience a significant decrease of pain symptoms. Nevertheless, a few patients seem resistant to this therapy, exhibiting no clear decrease in pain sensation.

    Therefore, we have in this pilot study investigated biopsies from the patellar tendon of one such therapy-resistant patient (male, exhibiting long duration of pain symptoms and showing radiological findings confirming tendinosis), using immunohistochemical methods examining both chemically fixed and unfixed tissue. The results were compared with our previous findings of both normal and tendinosis tendons.

    Morphologically, there was hypercellularity in the tendon tissue. The immunohistochemical studies showed that there were marked immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) (fixed tissue), as well as for the M2 muscarinic acetylcholine receptor (unfixed tissue), in the overwhelming majority of the tenocytes. The levels of immunoreactions were more pronounced than those obtained in the tendinosis tissue of the previously studied patients and clearly more pronounced than those of tendon tissue of controls.

    In conclusion, our theory is that cases of severe tendinosis, exhibiting therapy-resistance, are related to the occurrence of an excessive local acetylcholine (ACh) production that appears to be even more prominent than in tendinosis in general. This case study emphasizes the need for further investigation regarding the role of non-neuronal ACh in therapy-resistant patellar tendon tendinosis.

  • 78.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Findings favoring production of non-neuronal acetylcholine with possible autocrine/paracrine effects in chronic painful patellar tendon tendinosis.2006Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The innervation pattern of the human patellar tendon is largely unknown. That includes the situation for patients suffering from patellar tendon tendinosis (“jumper’s knee”). Concerning the possible occurrence of a cholinergic system in the human patellar tendon, very little information is available.

    In the present study, specimens of pain-free normal (n=16) and chronically painful tendinosis (n=7) tendons were examined by different immunohistochemical and histochemical methods.

    It was found that parts of the tenocytes of the tendinosis tendons displayed immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT). Furthermore, immunoreactions for the M2 muscarinic acetylcholine receptor could be detected in both blood vessel cells and tenocytes, especially in tendinosis specimens. Acetylcholinesterase activity was shown for scarce nerve fibers associated with small blood vessels in both the normal and the tendinosis tendons.

    The observations suggest that, besides the occurrence of a scanty nerve related cholinergic system in the human patellar tendon, there is a local non-neuronal cholinergic system as well, at least in tendinosis tendons. As ChAT and VAChT were detected in tenocytes of these tendons, such tenocytes are likely to produce acetylcholine (ACh) locally, and as both tenocytes and blood vessel cells were found to express the M2 receptor, it is likely that both of these cell types may be influenced by ACh.

    Thus, in conclusion, there appears to be an upregulation of the cholinergic system, and an occurrence of autocrine/paracrine effects in this system, in the tendinosis patellar tendon. This observation is of importance, not only related to the fact that tendinosis patients exhibit marked pain, but also as stimulation of ACh receptors can lead to cell proliferation, effects on collagen accumulation and angiogenesis, all of which are phenomena that occur in tendinosis.

  • 79.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Immunohistochemical and histochemical findings favoring the occurrence of autocrine/paracrine as well as nerve-related cholinergic effects in chronic painful patellar tendon tendinosis.2006Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 69, nr 10, s. 808-819Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pathogenesis of the pain in patellar tendon tendinosis ("jumper's knee") is unclear. We have recently presented new information about the sensory nervous system in the human patellar tendon, but there is very little information regarding the possible occurrence of a cholinergic system in this tendon. In the present study, specimens of pain-free normal tendons and chronically painful tendinosis tendons were examined by different immunohistochemical and histochemical methods. Antibodies against the M(2) receptor, choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT) were applied, and staining for demonstration of activity of acetylcholinesterase (AChE) was also utilized. It was found that immunoreactions for the M(2) receptor could be detected intracellularly in both blood vessel cells and tenocytes, especially in tendinosis specimens. Furthermore, in the tendinosis specimens, some tenocytes were seen to exhibit immunoreaction for ChAT and VAChT. AChE reactions were seen in fine nerve fibers associated with small blood vessels in both the normal control tendons and the tendinosis tendons. The observations suggest that there is both a nerve related and a local cholinergic system in the human patellar tendon. As ChAT and VAChT immunoreactions were detected in tenocytes of tendinosis tendons, these cells might be a source of local acetylcholine (Ach) production. As both tenocytes and blood vessel cells were found to exhibit immunoreactions for the M(2) receptor, it is likely that both of these tissue cells may be influenced by ACh. Thus, in conclusion, there appears to be an upregulation of the cholinergic system, and an occurrence of autocrine/paracrine effects in this system, in the tendinosis patellar tendon.

  • 80.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    In situ hybridization studies confirming recent findings of the existence of a local nonneuronal catecholamine production in human patellar tendinosis.2007Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 70, nr 10, s. 908-911Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    We have in recent studies presented unexpected immunohistochemical evidence favoring the existence of a local production of catecholamines, and an occurrence of adrenergic receptors on the tendon cells (tenocytes), in the human patellar tendon. This was particularly noticed for tendons from patients suffering from tendinosis (chronic tendon pain), which has led us to propose an involvement of this autocrine/paracrine system in the development of tendinosis, especially since catecholamines have been reported to be modulators of tissue remodeling and pain processes. However, the findings concerning catecholamine production have so far only been noted at the level of protein detection, and for this reason, the aim of the present study was to confirm the previous immunohistochemical results by using in situ hybridization (ISH) technique. A ssDNA probe detecting human mRNA for the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) was applied. The ISH results revealed that there were clear reactions indicating the existence of mRNA for TH in tenocytes of tendinosis specimens. It was generally noted that disfigured tenocytes were the ones with the most distinct reactions, while normally looking tenocytes hardly displayed any reactions at all. In conclusion, this study presents the first evidence at the mRNA level of the existence of a local nonneuronal production of catecholamines in human patellar tendon tissue. The findings add to recent observations of the occurrence of a local production in tendons of signal substances traditionally related to neurons.

    (c) 2007 Wiley-Liss, Inc.

  • 81.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Marked occurrence of receptors for sympathetic and cholinergic transmitters and for substance P in the blood vessels of the human patellar tendon.2005Konferansepaper (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Human tendons have generally been considered to be hyponeural. However, in our recent studies of the patellar tendon in both healthy individuals and patients with tendinosis (jumper’s knee), we have noted the presence of general (PGP 9.5) and sensory (substance P [SP]) innervations, especially in the loose paratendinous connective tissue. Furthermore, we have observed a pronounced expression of the neurokinin-1 receptor (the preferred receptor for SP) in blood vessel walls. The findings are of interest as a new successful treatment of tendinosis has emerged in form of doppler guided sclerosing injections (substance: Polidokanol), targeting areas with neovascularisation, and as SP is known to be of importance when neurogenic angiogenesis participates in diseases. AIM: To further investigate the blood vessels of the normal and tendinosis-affected human patellar tendon regarding autonomic innervation. METHODS: Immunohistochemistry and histochemistry, including antibodies against the sympathetic nerve markers tyroxine hydroxylase and neuropeptide Y and against various adrenoreceptors (α1, α2a, β1), as well as stainings for substances related to cholinergic functions such as the muscarinic M2 receptor, acetylcholinesterase and vesicular acetylcholine transporter. RESULTS/CONCLUSIONS: The preliminary results so far, indicate that there is indeed an occurrence of both sympathetic and cholinergic innervations in the tendon, not the least shown via the presence of sympathetic and cholinergic receptors in blood vessel walls; a fact that further supports the theories that blood vessel regulation via neurotransmitters/-modulators might be a key factor in the pathological mechanisms of jumper’s knee.

  • 82.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man.2007Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 70, nr 4, s. 310-324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changes in the patterns of production and in the effects of signal substances may be involved in the development of tendinosis, a chronic condition of pain in human tendons. There is no previous information concerning the patterns of sympathetic innervation in the human patellar tendon. In this study, biopsies of normal and tendinosis patellar tendons were investigated with immunohistochemical methods, including the use of antibodies against tyrosine hydroxylase (TH) and neuropeptide Y, and against alpha(1)-, alpha(2A)-, and beta(1)-adrenoreceptors. It was noticed that most of the sympathetic innervation was detected in the walls of the blood vessels entering the tendon through the paratendinous tissue, and that the tendon tissue proper of the normal and tendinosis tendons was very scarcely innervated. Immunoreactions for adrenergic receptors were noticed in nerve fascicles containing both sensory and sympathetic nerve fibers. High levels of these receptors were also detected in the blood vessel walls; alpha(1)-adrenoreceptor immunoreactions being clearly more pronounced in the tendinosis tendons than in the tendons of controls. Interestingly, immunoreactions for adrenergic receptors and TH were noted for the tendon cells (tenocytes), especially in tendinosis tendons. The findings give a morphological correlate for the occurrence of sympathetically mediated effects in the patellar tendon and autocrine/paracrine catecholamine mechanisms for the tenocytes, particularly, in tendinosis. The observation of adrenergic receptors on tenocytes is interesting, as stimulation of these receptors can lead to cell proliferation, degeneration, and apoptosis, events which are all known to occur in tendinosis. Furthermore, the results imply that a possible source of catecholamine production might be the tenocytes themselves. Microsc. Res. Tech., 2007. (c) 2007 Wiley-Liss, Inc.

  • 83.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Andersson, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Extensive expression of markers for acetylcholine synthesis and of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendinosis - a pilot study.2007Inngår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 80, nr 24-25, s. 2235-2238Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have recently obtained evidence favoring the occurrence of an up-regulation of a non-neuronal cholinergic system in chronic painful patellar tendon tendinosis. It seems possible that this up-regulation to a certain degree may be involved in the manifestations of the disease. Today, there is a new, very successful, line of treatment of patellar tendinosis in the form of Doppler guided sclerosing injections. However, a few patients seem resistant to this therapy. Therefore, we have in this pilot study investigated biopsies from the patellar tendon of three such therapy-resistant patients, using immunohistochemistry. In situ hybridization was also applied. Comparisons were made with a material of specimens from both normal (n=16) and tendinosis (n=7) tendons, also previously examined. The study showed that there were extensive immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter, as well as for the M(2) muscarinic acetylcholine receptor, in the overwhelming majority of the tenocytes. The immunoreactions were more pronounced than those generally obtained in the tendinosis tissue of the previously studied patients and clearly more pronounced than those of patellar tendon tissue of controls. Also, for the first time, we here present findings of mRNA for ChAT within tenocytes. In conclusion, it appears as if there is an excessive local acetylcholine (ACh) production and an occurrence of marked ACh effects in cases of severe tendinosis. An excessive production of local ACh might be related to pain sensation and the processes that occur in tendinosis development, such as cell proliferation. Thus, the results of this pilot study suggest that non-neuronal ACh is highly involved in the pathology of therapy-resistant patellar tendinosis.

  • 84.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Andersson, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Marked sympathetic component in the perivascular innervation of the dorsal paratendinous tissue of the patellar tendon in arthroscopically treated tendinosis patients.2008Inngår i: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 16, nr 6, s. 621-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During the recent years, a few studies have shed new light on the innervation patterns of the human patellar tendon, but the area of the loose paratendinous connective tissue dorsal to the proximal tendon proper has yet not been investigated. That is a drawback, since this is the area targeted in promising treatment regimens of chronic painful patellar tendinosis, namely sclerosing Polidocanol injection therapy, and a new surgical method conforming to ultrasound and color Doppler guided arthroscopic shaving, directed at neovessels found in the region. The present study thus aimed at investigating the paratendinous area dorsal to the proximal patellar tendon proper in seven patients being operated for tendinosis. Biopsies were collected through the new arthroscopic technique, approaching the tendon from the dorsal side. Samples were investigated using immunohistochemistry with antibodies delineating general (PGP 9.5), sensory (SP/CGRP), and sympathetic (TH/NPY) nerve patterns, and also antibodies against alpha1- and alpha2A-adrenoreceptors. Both small and large blood vessels had a marked perivascular innervation (PGP 9.5). Surprisingly, this perivascular innervation was found only to a very limited extent to correspond to sensory nerves, while there were marked immunoreactions for sympathetic markers. Adrenoreceptor immunoreactions frequently occurred in blood vessel walls. In conclusion, this study demonstrates, for the first time, the innervation patterns of the area dorsal to the patellar tendon in man. It shows that the area investigated is under marked influence by the sympathetic nervous system. Thus, sympathetic effects are likely to occur for blood vessels of the area, which is interesting since color Doppler has revealed that vessels of this area ("neovessels") display a pathologically high blood flow in tendinosis. The findings are discussed in relation to aspects of vascular regulation, and to pain symptoms of tendinosis.

  • 85.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Scott, Alex
    Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada.
    Teaming up to beat tendon pain: clinical and research excellence own the podium at ISTS (International Scientific Tendinopathy Symposium).2013Inngår i: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 47, nr 9, s. 532-532Artikkel i tidsskrift (Fagfellevurdert)
  • 86. Dardevet, Dominique
    et al.
    Savary-Auzeloux, Isabelle
    Remond, Didier
    Mosoni, Laurent
    Marzetti, Emanuele
    Buford, Thomas W
    Bernabei, Roberto
    Dionne, Isabelle J
    Buford, Thomas W
    Marzetti, Emanuele
    Manini, Todd M
    Buehring, Bjoern
    Kirchner, Elizabeth
    Calabrese, Leonard
    Manini, Todd M
    Clark, Brian C
    Fonseca, Helder M
    Delbono, Osvaldo
    Taylor, Jackson R
    Aubertin-Leheudre, Mylène
    Barbat-Artigas, Sébastien
    Pion, Charlotte H
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Gustafsson, Thomas
    Cederholm, Tommy
    Ulfhake, Brun
    Commentaries on Viewpoint: muscle atrophy is not always sarcopenia.2012Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 113, nr 4, s. 680-684Artikkel i tidsskrift (Fagfellevurdert)
  • 87. Di, Guohu
    et al.
    Qi, Xia
    Zhao, Xiaowen
    Zhang, Songmei
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhou, Qingjun
    Corneal Epithelium-Derived Neurotrophic Factors Promote Nerve Regeneration2017Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 58, nr 11, s. 4695-4702Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE. To explore the neurotrophic factor expression in corneal epithelium and evaluate their effects on the trigeminal ganglion (TG) neurite outgrowth and corneal nerve regeneration in mice. METHODS. The expression of neurotrophic factors was compared among the intact, regenerating, and regenerated mouse corneal epithelium. Mouse primary TG neurons were treated with the conditioned medium of mouse corneal epithelial cells. Nerve growth factor (NGF) neutralizing antibody and glial cell-derived neurotrophic factor (GDNF) neutralizing antibody were used to evaluate their roles in mouse corneal nerve regeneration and TG neurite outgrowth. The promoting effects of NGF and GDNF for the corneal nerve regeneration were further evaluated in the diabetic mice. RESULTS. The expression of NGF and GDNF showed significant up-regulation in regenerating corneal epithelium and return to the preinjury levels in the regenerated epithelium, which was consistent with the progress of corneal subbasal nerve regeneration. The conditioned medium of corneal epithelial cells promoted the TG neurite outgrowth with extended branching and elongation. Furthermore, the blockage of either NGF or GDNF significantly impaired the promotion of the neurite outgrowth by the conditioned medium or the corneal nerve regeneration in normal mice. Moreover, the expression of NGF and GDNF was attenuated in the diabetic regenerating corneal epithelium as compared to that in normal mice, while exogenous NGF or GDNF supplement promoted the corneal epithelial and nerve regeneration in diabetic mice. CONCLUSIONS. Corneal epithelium expresses multiple neurotrophic factors, among which NGF and GDNF may play an important role in the corneal nerve regeneration.

  • 88.
    di Summa, Pietro G
    et al.
    University Hospital of Lausanne, University of Manchester.
    Kalbermatten, Daniel F
    University Hospital of Lausanne, University Hospital of Basel.
    Pralong, E
    University Hospital of Lausanne.
    Raffoul, W
    University Hospital of Lausanne.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Terenghi, Giorgio
    University of Manchester.
    Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts2011Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 181, nr 5, s. 278-291Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although autologous nerve graft is still the first choice strategy in nerve reconstruction, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to improve nerve regeneration. Nerve fibrin conduits were seeded with various cell types: primary Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC). Two further control groups were fibrin conduits without cells and autografts. Conduits were used to bridge a 1 cm rat sciatic nerve gap in a long term experiment (16 weeks). Functional and morphological properties of regenerated nerves were investigated. A reduction in muscle atrophy was observed in the autograft and in all cell-seeded groups, when compared with the empty fibrin conduits. SC showed significant improvement in axon myelination and average fiber diameter of the regenerated nerves. dASC were the most effective cell population in terms of improvement of axonal and fiber diameter, evoked potentials at the level of the gastrocnemius muscle and regeneration of motoneurons, similar to the autografts. Given these results and other advantages of adipose derived stem cells such as ease of harvest and relative abundance, dASC could be a clinically translatable route towards new methods to enhance peripheral nerve repair.

  • 89.
    di Summa, Pietro G
    et al.
    University of Manchester, University Hospital of Lausanne.
    Kalbermatten, Daniel F
    University Hospital of Basel.
    Raffoul, Wassim
    University Hospital of Lausanne.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University of Manchester.
    Extracellular matrix molecules enhance the neurotrophic effect of Schwann cell-like differentiated adipose-derived stem cells and increase cell survival under stress conditions2013Inngår i: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 19, nr 3-4, s. 368-379Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Since the first reports of induction of adipose-derived stem cells (ASC) into neuronal and glial cell phenotypes, expectations have increased regarding their use in tissue engineering applications for nerve repair. Cell adhesion to extracellular matrix (ECM) is a basic feature of survival, differentiation, and migration of Schwann cells (SC) during nerve regeneration, and fibronectin and laminin are two key molecules of this process. Interaction between ECM and SC-like differentiated ASC (dASC) could potentially improve the neurotrophic potential of the stem cells. We have investigated the effect of ECM molecules on SC-like dASC in terms of proliferation, adhesion, and cell viability. Fibronectin and laminin did not affect the proliferation of dASC when compared with cell adherent tissue culture plastic, but significantly improved viability and cell attachment when dASC were exposed to apoptotic conditions. To assess the influence of the ECM molecules on dASC neurotrophic activity, dASC were seeded onto ECM-coated culture inserts suspended above dorsal root ganglia (DRG) sensory neurons. Neurite outgrowth of DRG neurons was enhanced when dASC were seeded on fibronectin and laminin when compared with controls. When DRG neurons and dASC were in direct contact on the various surfaces there was significantly enhanced neurite outgrowth and coculture with laminin-conditioned dASC produced the longest neurites. Compared with primary SCs, dASC grown on laminin produced similar levels of neurite outgrowth in the culture insert experiments but neurite length was shorter in the direct contact groups. Anti beta 1 integrin blocking antibody could inhibit baseline and dASC evoked neurite elongation but had no effect on outgrowth mediated by laminin-conditioned dASC. ECM molecules had no effect on the levels of nerve growth factor and brain-derived neurotrophic factor secretion from dASC. The results of the study suggest that ECM molecules can significantly improve the potential of dASC for nerve regeneration.

  • 90.
    di Summa, Pietro G.
    et al.
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland. Electronic address: Pietro.Di-Summa@chuv.ch..
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Campisi, Corrado C.
    Department of Plastic, Reconstructive Surgery, University Hospital of Genova, Ospedale S. Martino, Largo Rossana Benzi 10, 16132 Genova, Italy.
    Raffoul, Wassim
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland.
    Kalbermatten, Daniel F.
    Department of Plastic, Reconstructive Surgery, University Hospital of Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland.
    Collagen (NeuraGen(®)) nerve conduits and stem cells for peripheral nerve gap repair2014Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 572, s. 26-31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Collagen nerve guides are used clinically for peripheral nerve defects, but their use is generally limited to lesions up to 3cm. In this study we combined collagen conduits with cells as an alternative strategy to support nerve regeneration over longer gaps. In vitro cell adherence to collagen conduits (NeuraGen(®) nerve guides) was assessed by scanning electron microscopy. For in vivo experiments, conduits were seeded with either Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC) or left empty (control group), conduits were used to bridge a 1cm gap in the rat sciatic nerve and after 2-weeks immunohistochemical analysis was performed to assess axonal regeneration and SC infiltration. The regenerative cells showed good adherence to the collagen walls. Primary SC showed significant improvement in distal stump sprouting. No significant differences in proximal regeneration distances were noticed among experimental groups. dMSC and dASC-loaded conduits showed a diffuse sprouting pattern, while SC-loaded showed an enhanced cone pattern and a typical sprouting along the conduits walls, suggesting an increased affinity for the collagen type I fibrillar structure. NeuraGen(®) guides showed high affinity of regenerative cells and could be used as efficient vehicle for cell delivery. However, surface modifications (e.g. with extracellular matrix molecule peptides) of NeuraGen(®) guides could be used in future tissue-engineering applications to better exploit the cell potential.

  • 91.
    di Summa, Pietro G
    et al.
    Chirurgie Plastique et Reconstructive CHUV, Université de Lausanne, Rue de Bugnon 46, 1005 Lausanne, CH, Switzerland.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Raffoul, W
    Chirurgie Plastique et Reconstructive CHUV, Université de Lausanne, Rue de Bugnon 46, 1005 Lausanne, CH, Switzerland.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratories. The University of Manchester, Manchester, UK.
    Kalbermatten, Daniel F
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Adipose-derived stem cells enhance peripheral nerve regeneration2010Inngår i: Journal of plastic, reconstructive and aesthetic surgery, ISSN 1878-0539, Vol. 63, nr 9, s. 1544-1552Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Traumatic injuries resulting in peripheral nerve lesions often require a graft to bridge the gap. Although autologous nerve auto-graft is still the first-choice strategy in reconstructions, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to create a favourable environment for nerve regeneration. We decided to test new fibrin nerve conduits seeded with various cell types (primary Schwann cells and adult stem cells differentiated to a Schwann cell-like phenotype) for repair of sciatic nerve injury. Two weeks after implantation, the conduits were removed and examined by immunohistochemistry for axonal regeneration (evaluated by PGP 9.5 expression) and Schwann cell presence (detected by S100 expression). The results show a significant increase in axonal regeneration in the group of fibrin seeded with Schwann cells compared with the empty fibrin conduit. Differentiated adipose-derived stem cells also enhanced regeneration distance in a similar manner to differentiated bone marrow mesenchymal stem cells. These observations suggest that adipose-derived stem cells may provide an effective cell population, without the limitations of the donor-site morbidity associated with isolation of Schwann cells, and could be a clinically translatable route towards new methods to enhance peripheral nerve repair.

  • 92.
    East, Emma
    et al.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Johns, Noémie
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Georgiou, Melanie
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Golding, Jon P.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Loughlin, A. Jane
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Phillips, James B.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK, Department of Biomaterials & Tissue Engineering, UCL Eastman Dental Institute, 256 Gray’s Inn Road, London WC1X 8LD, UK.
    A 3D in vitro model reveals differences in the astrocyte response elicited by potential stem cell therapies for CNS injury2013Inngår i: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 8, nr 6, s. 739-746Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success.

    MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control.

    RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent.

    CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.

  • 93.
    Edman, Anne-Christine
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Myofibrillens finstruktur i tvärstrimmig skelettmuskulatur1988Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The detailed structure of the myofibrillar material in fibres from different muscles has been studied. Specimens have been obtained from human muscles and from different muscles frequently examined in experimental studies. Both light- and electron microscopical techniques have been used. Of central importance has been the method, which makes it possible to prepare ultrathin sections of frozen tissue, i.e. cryo-ult- ramicrotomy. A number of techniques for image analysis have been applied in order to obtain objektive data from the micrographs.

    In Paper I the present knowledge about muscle fibre structure, cryo-- sectioning and image analysis is summarized and relevant methodological problems are discussed. Paper II describes the detailed structure of the C-zone of the A-band and shows, above all, that structures occur with different repeats along the long axis of the myofibril. Paper III describes the subcellular organization of different fibres in a homogeneous (based on enzyme histochemical mATPase) population, and shows that different structural characteristies can vary independently of each other. Paper IV describes the structural diversity of the myofibrillar M-band, and paper V the diversity of the myofilament fine structure in different fibres. The results show that there is a most sophisticated, and previosly unrealized, structural specialization both within the myofibrils and between myofibrils from different fibres and muscles, even if the fibres are of the same fibre type. The findings suggest that generally used models, showing the structural organization within myofibrils and myofilaments, are oversimplifications. The fibre population is more heterogeneously built up than the common systems for fibre type classification makes one to belive.

  • 94.
    Edmundsson, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Toolanen, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Stål, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Muscle changes in diabetics with chronic compartment syndromeManuskript (preprint) (Annet vitenskapelig)
  • 95.
    Edmundsson, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Toolanen, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Stål, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Evidence for low muscle capillary supply as a pathogenic factor in chronic compartment syndrome2010Inngår i: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 20, nr 6, s. 805-813Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is a paucity of data regarding the pathogenesis of chronic exertional compartment syndrome (CECS), its consequences for the muscles and the effects of treatment with fasciotomy. We analyzed biopsies from the tibialis anterior muscle, from nine patients, obtained during a decompressing fasciotomy and during follow-up 1 year later. Control biopsies were obtained from nine normal subjects. Muscle capillarity, fiber-type composition and fiber area were analyzed with enzyme- and immunohistochemistry and morphometry. At baseline, CECS patients had lower capillary density (273 vs 378 capillaries/mm(2), P=0.008), lower number of capillaries around muscle fibers (4.5 vs 5.7, P=0.004) and lower number of capillaries in relation to the muscle fiber area (1.1 vs 1.5, P=0.01) compared with normal controls. The fiber-type composition and fiber area did not differ, but focal signs of neuromuscular damage were observed in the CECS samples. At 1-year follow-up after fasciotomy, the fiber area and the number of fibers containing developmental myosin heavy chains were increased, but no enhancement of the capillary network was detected. Thus, morphologically, patients with CECS seemed to have reduced microcirculation capacity. Fasciotomy appeared to trigger a regenerative response in the muscle, however, without any increase in the capillary bed.

  • 96. Ekblom, B
    et al.
    Ekblom, O
    Malm, Christer
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi.
    Infectious episodes before and after a marathon race.2006Inngår i: Scandinavian Journal of Medicine & Science in Sports, ISSN 0905-7188, Vol. 16, nr 4, s. 287-93Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to investigate the incidence of self-reported infectious episodes (IE) during 3 weeks before (pre-IE) and 3 weeks after (post-IE) a marathon race and relate these figures to training status, running time, socioeconomic and demographic factors. Two questionnaires, including questions about important factors for IE incidence, were given to a representative cohort of 1694 runners (17% of all finishers) in the Stockholm Marathon 2000. Pre-IE incidence in the cohort was 17% with no difference between women and men. Post-IE incidence in the whole cohort was 19% with no significant (P>0.05) difference between women and men. The post-IE incidence in runners without a pre-IE was 16% (P>0.05 to pre-IE incidence). In the group of runners with pre-IE, 33% experienced an IE after the race also (P<0.05 to Pre-IE incidence). A logistic regression analysis showed that younger age and pre race health status and, for men only, experienced nausea during and after the race were depended factors explaining post-IE incidence. Younger runners were more prone to experience IE both before and after the race. There was no relation between training volume 6 months before the race, finishing time and socioeconomic and demographic factors and pre-IE or post-IE. This study does not support the theory of increased infection rate after exhaustive long-distance running ("The Open Window Theory") in recreational runners, but suggests that the sometimes experienced increased rate of infections among athletes can be caused by strenuous exercise too soon after an infection.

  • 97.
    El-Habta, Roine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Chen, Jialin
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Pingel, Jessica
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Tendinosis-like changes in denervated rat Achilles tendon2018Inngår i: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 19, artikkel-id 426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Tendon disorders are common and lead to significant disability and pain. Our knowledge of the ‘tennis elbow’, the ‘jumpers knee’, and Achilles tendinosis has increased over the years, but changes in denervated tendons is yet to be described in detail. The aim of the present study was to investigate the morphological and biochemical changes in tendon tissue following two weeks of denervation using a unilateral sciatic nerve transection model in rat Achilles tendons.

    Methods: Tendons were compared with respect to cell number, nuclear roundness, and fiber structure. The non-denervated contralateral tendon served as a control. Also, the expression of neuromodulators such as substance P and its preferred receptor neurokinin-1 receptor, NK-1R, was evaluated using real-time qRT-PCR.

    Results: Our results showed that denervated tendons expressed morphological changes such as hypercellularity; disfigured cells; disorganization of the collagen network; increased production of type III collagen; and increased expression of NK-1R.

    Conclusion: Taken together these data provide new insights into the histopathology of denervated tendons showing that denervation causes somewhat similar changes in the Achilles tendon as does tendinosis in rats.

  • 98.
    El-Habta, Roine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Adipose stem cells enhance myoblast proliferation via acetylcholine and extracellular signal-regulated kinase 1/2 signaling2018Inngår i: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 57, nr 2, s. 305-311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: In this study we investigated the interaction between adipose tissue-derived stem cells (ASCs) and myoblasts in co-culture experiments. Methods: Specific inductive media were used to differentiate ASCs in vitro into a Schwann cell-like phenotype (differentiated adipose tissuederived stem cells, or dASCs) and, subsequently, the expression of acetylcholine (ACh)-related machinery was determined. In addition, the expression of muscarinic ACh receptors was examined in denervated rat gastrocnemius muscles. Results: In contrast to undifferentiated ASCs, dASCs expressed more choline acetyltransferase and vesicular acetylcholine transporter. When co-cultured with myoblasts, dASCs enhanced the proliferation rate, as did ACh administration alone. Western blotting and pharmacological inhibitor studies showed that phosphorylated extracellular signal-regulated kinase 1/2 signaling mediated these effects. In addition, denervated muscle showed higher expression of muscarinic ACh receptors than control muscle. Discussion: Our findings suggest that dASCs promote proliferation of myoblasts through paracrine secretion of ACh, which could explain some of their regenerative capacity in vivo.

  • 99.
    El-Habta, Roine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Sloniecka, Marta
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The adipose tissue stromal vascular fraction secretome enhances the proliferation but inhibits the differentiation of myoblasts2018Inngår i: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 9, artikkel-id 352Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Adipose tissue is an excellent source for isolation of stem cells for treating various clinical conditions including injuries to the neuromuscular system. Many previous studies have focused on differentiating these adipose stem cells (ASCs) towards a Schwann cell-like phenotype (dASCs), which can enhance axon regeneration and reduce muscle atrophy. However, the stromal vascular fraction (SVF), from which the ASCs are derived, also exerts broad regenerative potential and might provide a faster route to clinical translation of the cell therapies for treatment of neuromuscular disorders.

    Methods: The aim of this study was to establish the effects of SVF cells on the proliferation and differentiation of myoblasts using indirect co-culture experiments. A Growth Factor PCR Array was used to compare the secretomes of SVF and dASCs, and the downstream signaling pathways were investigated.

    Results: SVF cells, unlike culture-expanded dASCs, expressed and secreted hepatocyte growth factor (HGF) at concentrations sufficient to enhance the proliferation of myoblasts. Pharmacological inhibitor studies revealed that the signal is mediated via ERK1/2 phosphorylation and that the effect is significantly reduced by the addition of 100 pM Norleual, a specific HGF inhibitor. When myoblasts were differentiated into multinucleated myotubes, the SVF cells reduced the expression levels of fast-type myosin heavy chain (MyHC2) suggesting an inhibition of the differentiation process.

    Conclusions: In summary, this study shows the importance of HGF as a mediator of the SVF effects on myoblasts and provides further evidence for the importance of the secretome in cell therapy and regenerative medicine applications.

  • 100.
    Engels, Patricia E.
    et al.
    University Hospital Basel.
    Tremp, Mathias
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    di Summa, Pietro G.
    Largo, Rene D.
    Schaefer, Dirk J.
    Kalbermatten, Daniel F
    Harvest site influences the growth properties of adipose derived stem cells2013Inngår i: Cytotechnology (Dordrecht), ISSN 0920-9069, E-ISSN 1573-0778, Vol. 65, nr 3, s. 437-445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The therapeutic potential of adult stem cells may become a relevant option in clinical care in the future. In hand and plastic surgery, cell therapy might be used to enhance nerve regeneration and help surgeons and clinicians to repair debilitating nerve injuries. Adipose-derived stem cells (ASCs) are found in abundant quantities and can be harvested with a low morbidity. In order to define the optimal fat harvest location and detect any potential differences in ASC proliferation properties, we compared biopsies from different anatomical sites (inguinal, flank, pericardiac, omentum, neck) in Sprague-Dawley rats. ASCs were expanded from each biopsy and a proliferation assay using different mitogenic factors, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) was performed. Our results show that when compared with the pericardiac region, cells isolated from the inguinal, flank, omental and neck regions grow significantly better in growth medium alone. bFGF significantly enhanced the growth rate of ASCs isolated from all regions except the omentum. PDGF had minimal effect on ASC proliferation rate but increases the growth of ASCs from the neck region. Analysis of all the data suggests that ASCs from the neck region may be the ideal stem cell sources for tissue engineering approaches for the regeneration of nervous tissue.

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