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Aging effect on neurotrophic activity of human mesenchymal stem cells
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. (Neurogruppen)
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. (Neurogruppen)
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. (Neurogruppen)
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. (Neurogruppen)
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2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 9, s. e45052-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Clinical efficacy of stem cells for nerve repair is likely to be influenced by issues including donor age and in vitro expansion time. We isolated human mesenchymal stem cells (MSC) from bone marrow of young (16–18 years) and old (67–75 years) donors and analyzed their capacity to differentiate and promote neurite outgrowth from dorsal root ganglia (DRG) neurons. Treatment of MSC with growth factors (forskolin, basic fibroblast growth factor, platelet derived growth factor-AA and glial growth factor-2) induced protein expression of the glial cell marker S100 in cultures from young but not old donors. MSC expressed various neurotrophic factor mRNA transcripts. Growth factor treatment enhanced the levels of BDNF and VEGF transcripts with corresponding increases in protein release in both donor cell groups. MSC in co-culture with DRG neurons significantly enhanced total neurite length which, in the case of young but not old donors, was further potentiated by treatment of the MSC with the growth factors. Stem cells from young donors maintained their proliferation rate over a time course of 9 weeks whereas those from the old donors showed increased population doubling times. MSC from young donors, differentiated with growth factors after long-term culture, maintained their ability to enhance neurite outgrowth of DRG. Therefore, MSC isolated from young donors are likely to be a favourable cell source for nerve repair.

Ort, förlag, år, upplaga, sidor
San Francisco: Public Library of Science , 2012. Vol. 7, nr 9, s. e45052-
Nyckelord [en]
adult stem cell, glia, nerve injury, regeneration
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
anatomi; cellforskning
Identifikatorer
URN: urn:nbn:se:umu:diva-47755DOI: 10.1371/journal.pone.0045052ISI: 000309742800031OAI: oai:DiVA.org:umu-47755DiVA, id: diva2:444337
Tillgänglig från: 2011-09-28 Skapad: 2011-09-28 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Mesenchymal stem cells for repair of the peripheral and central nervous system
Öppna denna publikation i ny flik eller fönster >>Mesenchymal stem cells for repair of the peripheral and central nervous system
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Odlade mesenkymala stamcellers användning vid skador på perifera och centrala nervsystemet
Abstract [en]

Bone marrow-derived mesenchymal stem cells (MSC) have been shown to provide neuroprotection after transplantation into the injured nervous system. The present thesis investigates whether adult human and rat MSC differentiated along a Schwann cell lineage could increase their expression of neurotrophic factors and promote regeneration after transplantation into the injured peripheral nerve and spinal cord.

Human and rat mesenchymal stem cells (hMSC and rMSC) expressed characteristic stem cell surface markers, mRNA transcripts for different neurotrophic factors and demonstrated multi-lineage differentiation potential. Following treatment with a cocktail of growth factors, the hMSC and rMSC expressed typical Schwann cells markers at both the transcriptional and translational level and significantly increased production of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF).

Age and time in culture are of relevance for clinical settings and growth-promoting effects of hMSC from young donors (16-18 years) and old donors (67-75 years) were compared. Undifferentiated hMSC from both young and old donors increased total neurite length of cultured dorsal root ganglion (DRG) neurons. Differentiation of hMSC from the young donors, but not the eldery donors, further enhanced the neurite outgrowth. Undifferentiated hMSC were cultured for eleven weeks in order to examine the effect of in vitro expansion time on neurite outgrowth. hMSC from the young donors maintained their proliferation rate and their ability to enhance neurite outgrowth from DRG neurons.

Using a sciatic nerve injury model, a 10mm gap was bridged with either an empty tubular fibrin glue conduit, or conduits containing hMSC, with and without cyclosporine treatment. Cells were labeled with PKH26 prior to transplantation. At 3 weeks after injury the conduits with cells and immunosuppression increased regeneration compared with an empty conduit. PKH26 labeled human cells survived in the rat model and the inflammatory reaction could be suppressed by cyclosporine.

After cervical C4 hemisection, BrdU/GFP-labeled rMSC were injected into the lateral funiculus rostral and caudal to the spinal cord lesion site. Spinal cords were analyzed 2-8 weeks after transplantation. Transplanted MSC remained at the injection sites and in the trauma zone for several weeks and were often associated with numerous neurofilament-positive axons. Transplanted rMSC induced up-regulation of vascular endothelial growth factor in spinal cord tissue rostral to the injury site, but did not affect expression of brain-derived neurotrophic factor. Although rMSC provided neuroprotection for rubrospinal neurons and significantly attenuated astroglial and microglial reaction, cell transplantation caused aberrant sprouting of calcitonin gene-related peptide immunostained sensory axons in the dorsal horn.

In summary these results demonstrate that both rat and human MSC can be differentiated towards the glial cell lineage, and show functional characteristics similar to Schwann cells. hMSC from the young donors represent a more favorable source for neurotransplantation since they maintain proliferation rate and preserve their growth-promoting effects in long-term cultures. The data also suggest that differentiated MSC increase expression of neurotrophic factors and support regeneration after peripheral nerve and spinal cord injury.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2011. s. 59
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1433
Nyckelord
Bone marrow-derived stromal cells, Schwann cells, Peripheral nerve injury, Spinal cord injury, Neurotransplantation
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
anatomi; cellforskning
Identifikatorer
urn:nbn:se:umu:diva-47746 (URN)978-91-7459-240-5 (ISBN)
Disputation
2011-10-20, BiA201, Biologihuset, Umeå universitet, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-09-29 Skapad: 2011-09-28 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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