Abstract
We have investigated and compared the neurotrophic activity of human dental pulp stem cells (hDPSC), human bone marrow-derived mesenchymal stem cells (hBMSC) and human adipose-derived stem cells (hAMSC) on axotomised adult rat retinal ganglion cells (RGC) in vitro in order to evaluate their therapeutic potential for neurodegenerative conditions of RGC. Using the transwell system, RGC survival and length/number of neurites were quantified in coculture with stem cells in the presence or absence of specific Fc-receptor inhibitors to determine the role of NGF, BDNF, NT-3, VEGF, GDNF, PDGF-AA and PDGF-AB/BB in stem cell-mediated RGC neuroprotection and neuritogenesis. Conditioned media, collected from cultured hDPSC/hBMSC/hAMSC, were assayed for the secreted growth factors detailed above using ELISA. PCR array determined the hDPSC, hBMSC and hAMSC expression of genes encoding 84 growth factors and receptors. The results demonstrated that hDPSC promoted significantly more neuroprotection and neuritogenesis of axotomised RGC than either hBMSC or hAMSC, an effect that was neutralized after the addition of specific Fc-receptor inhibitors. hDPSC secreted greater levels of various growth factors including NGF, BDNF and VEGF compared with hBMSC/hAMSC. The PCR array confirmed these findings and identified VGF as a novel potentially therapeutic hDPSC-derived neurotrophic factor (NTF) with significant RGC neuroprotective properties after coculture with axotomised RGC. In conclusion, hDPSC promoted significant multi-factorial paracrine-mediated RGC survival and neurite outgrowth and may be considered a potent and advantageous cell therapy for retinal nerve repair.
Highlights
The axons of retinal ganglion cells (RGC) transmit action potentials along the optic nerve to the superior colliculus (SC) and lateral geniculate nucleus (LGN) that are relayed onwards to the visual cortex
The increase in survival of RGC in human dental pulp stem cells (hDPSC)-treated retinal cultures was significantly greater (p,0.05) than that achieved in cocultures with hAMSC (p,0.05) but not significantly greater than that seen in cocultures with human bone marrow-derived mesenchymal stem cells (hBMSC)
Coculture with hDPSC promoted a significant increase (p,0.05) in the number of neurite-bearing RGC as well as neurite length when compared with cocultures with hBMSC and hAMSC, or with retinal cultures exposed to recombinant nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3)
Summary
The axons of retinal ganglion cells (RGC) transmit action potentials along the optic nerve to the superior colliculus (SC) and lateral geniculate nucleus (LGN) that are relayed onwards to the visual cortex. The paucity of NTF in the central nervous system (CNS) is one explanation for the lack of axon regeneration compared to the peripheral nervous system (PNS) [2,7] in which successful and functional axon regeneration occurs, largely promoted by Schwann cell-derived NTF [8]. Attempts to promote long distance axon regeneration by the transplantation of peripheral nerve grafts into the CNS have met with some success [9]. Grafting a peripheral nerve into the vitreous body after optic nerve crush [8] promotes more RGC axon regeneration in the transected optic nerve than occurs after the removal of Schwann cells before transplantation, suggesting that axotomised RGC regenerate their axons when provided with a constant supply of NTF. Single NTF supplementation [7], or single dose treatments of NTF such as BDNF [10,11], have proven unsuccessful and sustained delivery of multiple NTF to RGC over extended periods of time is difficult to achieve
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