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Mesenchymal stem cells prolong the survival of xenogenic neurons in the brain

Philippe Naveilhan^1,2,3, Xavier Lévèque^1,2,3, Elodie Mathieux^1,2,3, Reynal Thinard^1,2,3, Laurent Lescaudron^1,2,3, Bernard Vanhove^1,2,3, Isabelle Neveu^1,2,3

¹U 643, INSERM; ²ITUN, CHU de nantes; ³UFR de médecine, Université de Nantes, Nantes, France

Cell transplantation is of great interest for the treatment of neurodegenerative diseases. Transplantation of human fetal neuroblasts in the brain of Parkinsonian’s patients has provided interesting results but tissue availability and ethical concerns limit this approach. An interesting alternative would be to use fetal pig neuroblasts (pNB) but xenogenic neurons are systematically rejected, even in the brain. Since mesenchymal stem cells (MSC) have potent immunosuppressive functions, we ask whether MSC could protect xenotransplanted neurons from rejection. To solve this issue, pNB or pNB+MSC were transplanted in the striatum of immunocompetent rats. In the pNb group, the graft was systematically rejected before 63 days, and the rejection process was associated with a local induction of proinflammatory molecules followed by a peak of anti-inflammatory cytokines. In the pNB+MSC group, 50% of the rats exhibited at 120 days, healthy grafts with porcine NF70 ⁺ neurons and dopaminergic cells (TH⁺). This long survival observed in the presence of MSC was associated with an inhibition of cytokine and chemokine induction and a prolonged upregulation of neurotrophic factors such as BDNF and GDNF. An active role of MSC in the long-term survival of pNB in the rat brain was supported by the fact that MSC protected pNB from cell death in culture and blocked T cell proliferation in vitro. To check that co-grafting strategy did not affect function of the transplant, MSC and pNB were co-transplanted into the striatum of 6-OHDA lesioned rats (model of Parkinson’s disease). Behavioral analyses showed motor recovery in the rats that had received MSC and pNB. Taken together, these data indicate that MSC are of great interest as a local immunosuppressive and neurotrophic agent in case of intracerebral transplantation.