Neural stem cell (NSCs) transplantation is a promising therapy for Multiple Sclerosis (MS). The clinical translation of such approach is limited by the lack of expandable autologous precursors. Induced pluripotent stem cells (iPSCs) may overcome this limitation. In our work we investigated whether the transplantation of NSCs derived from iPSCs (NS iPSCs) could represent a safe and effective therapeutic strategy in a mouse model of MS, namely experimental autoimmune encephalomyelitis (EAE). Methods: NS iPSCs were derived from iPSCs obtained by lentiviral reprogramming of mouse fibroblasts. EAE was induced in C57/BL6 mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein (MOG)35-55. At 25 days post immunization (dpi), EAE mice were intrathecally transplanted with GFP-labelled NS iPSCs. Neuropathology was assessed at 40 and 80 dpi while the influence of NS iPSCs on remyelination was further evaluated in vitro on primary oligodendrocyte precursor cell (OPC) cultures. Results: Upon transplantation in EAE mice, NS iPSCs did not induce any tumour formation and significantly reduced clinical severity, demyelination, axonal loss and neuroinflammation when compared to shamtreatment. Since transplanted NS iPSCs remained undifferentiated in close contact with perivascular inflammatory infiltrates, we investigated whether the inflammatory environment could induce NS iPSCs to promote endogenous repair mechanisms. Indeed we observed that, in vitro, the conditioned medium of NS iPSCs – challenged with inflammatory cytokines (IFNγ and TNFα) – markedly increased survival and differentiation of OPC primary cultures. This effect was not dependent on IFNγ or TNFα, as these cytokines alone were not able to sustain OPC survival. Conclusions: Our work provides the first evidence of the safety and efficacy of NS iPSCs in EAE. We showed that transplanted NS iPSCs exert their therapeutic bystander effect by persisting undifferentiated near the perivascular infiltrate. In vitro experiments suggest that the inflammatory environment could induce NS iPSC to secrete a variety of molecules that might promote endogenous remyelination.
Neural stem cells derived from iPSCs represent a safe and effective source for stem cell therapy in experimental autoimmune encephalomyelitis
ONORATI, MARCO;
2012-01-01
Abstract
Neural stem cell (NSCs) transplantation is a promising therapy for Multiple Sclerosis (MS). The clinical translation of such approach is limited by the lack of expandable autologous precursors. Induced pluripotent stem cells (iPSCs) may overcome this limitation. In our work we investigated whether the transplantation of NSCs derived from iPSCs (NS iPSCs) could represent a safe and effective therapeutic strategy in a mouse model of MS, namely experimental autoimmune encephalomyelitis (EAE). Methods: NS iPSCs were derived from iPSCs obtained by lentiviral reprogramming of mouse fibroblasts. EAE was induced in C57/BL6 mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein (MOG)35-55. At 25 days post immunization (dpi), EAE mice were intrathecally transplanted with GFP-labelled NS iPSCs. Neuropathology was assessed at 40 and 80 dpi while the influence of NS iPSCs on remyelination was further evaluated in vitro on primary oligodendrocyte precursor cell (OPC) cultures. Results: Upon transplantation in EAE mice, NS iPSCs did not induce any tumour formation and significantly reduced clinical severity, demyelination, axonal loss and neuroinflammation when compared to shamtreatment. Since transplanted NS iPSCs remained undifferentiated in close contact with perivascular inflammatory infiltrates, we investigated whether the inflammatory environment could induce NS iPSCs to promote endogenous repair mechanisms. Indeed we observed that, in vitro, the conditioned medium of NS iPSCs – challenged with inflammatory cytokines (IFNγ and TNFα) – markedly increased survival and differentiation of OPC primary cultures. This effect was not dependent on IFNγ or TNFα, as these cytokines alone were not able to sustain OPC survival. Conclusions: Our work provides the first evidence of the safety and efficacy of NS iPSCs in EAE. We showed that transplanted NS iPSCs exert their therapeutic bystander effect by persisting undifferentiated near the perivascular infiltrate. In vitro experiments suggest that the inflammatory environment could induce NS iPSC to secrete a variety of molecules that might promote endogenous remyelination.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
