Abstract
Objective: Neural progenitor cells (NPC) derived from human embryonic stem cells have the potential to differentiate into mature neurons after transplantation in the brain, opening the possibility of regenerative cell therapy for neurodegenerative disorders like Parkinson’s disease. For such therapy, the source of NPC is genetically unrelated to the patient, leading to potential rejection of the transplanted cells by the host’s immune response. Rejection can be prevented by the use of immunosuppressive drugs (ISD). Previous works have suggested that cyclosporine and dexamethasone used in classical immunosuppressive regimen could prevent the terminal differentiation of NPC into mature neurons depending on culture conditions. Methods: We have investigated in vitro the role of other ISD, Intra venous Immunoglobulins (IvIG), mycophenolate mofetil and tacrolimus. We have tested the immunosuppressive activity of tacrolimus and cyclosporine on the effector of natural killer (NK) and CD8+T-cells and performed a microarray to analyse the difference between the two drugs for the neuron differentiation. Finally, human transplanted neuroprecursor cell survival has been analyzed in rats treated with tacrolimus or cyclosporine and anti-inflammatory treatments. Results: IvIG and mycophenolate mofetil interfere with the development of NPC into mature neurons, but tacrolimus do not inhibit the maturation process of NPC. Microarray experiments demonstrate significant differences between cyclosporine and tacrolimus gene expression during NPC maturation into mature neurons. Tacrolimus like cyclosporine is able to inhibit the CD8+T-cells activation against neural progenitors, but both are unable to block NK cells activity. NK cells could be potential harmful weapons to reject NPC and mature neurons. In rats treated with both immunosuppressive (tacrolimus or cyclosporine) and anti-inflammatory treatments, engrafted human neuroprecursors cell survival is good and the microglial density is low. Conclusion: These data suggest in vivo that both tacrolimus and cyclosporine, with an
Highlights
Immense expectations surround the field of stem-cells transplantation
Intra venous Immunoglobulins (IvIG) and mycophenolate mofetil interfere with the development of Neural progenitor cells (NPC) into mature neurons, but tacrolimus do not inhibit the maturation process of NPC
These data suggest in vivo that both tacrolimus and cyclosporine, with an anti-inflammatory treatment like prednisolone, promote graft survival and minimise the host microglial response
Summary
Considering the potential risk of rejection by the recipient’s immune system, the source of stem cells has to be carefully evaluated Due to their various characteristics, human embryonic stem (hES) cells provide an excellent tool for transplantation. The most important attribute of hES cells is their pluripotency, since they can differentiate into the three different germ layers, i.e. endoderm, mesoderm and ectoderm, and they can be effective for all types of differentiated cells. Another advantage is their capacity to indefinitely proliferate in the appropriate culture conditions. Even though the potential of hES cells is huge, there are still many hurdles ahead before the clinical use of these cells
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