Human induced pluripotent stem cells for stem cell therapy in stroke

The potential of stem cell (SC) transplantation for the treatment of acute brain lesions has been highlighted by a number of experimental results. Among available cell sources, induced pluripotent stem cells (iPS) combine the advantages related to their similarities with embryonic stem cells (ESC), i.e., pluripotency, and self-renewal, with “à la carte” treatments. They also come with a number of potentially deleterious aspects for SC therapy that include overproliferation or abnormal differentiation due to genetic and epigenetic abnormalities. Neural progenitors (NP) were derived from 2 hiPS lines and 2 hESC lines with matching gender and were transplanted into adult Sprague-Dawley rats 7 days after a 90 min occlusion of the middle cerebral artery (MCAO). Animals were followed for behavioral tests and neurological scores and for magnetic resonance imaging (MRI) before and after MCAO, and after transplantation over 5 months. NPC from hiPSC and hESC had similar differentiation abilities in vitro, and displayed similar survival rate, integration and differentiation patterns after transplantation. Neurons with correct region-specific phenotype, i.e. striatal DARPP32-positive neurons, developed with time in the grafts, in correlation with months-lasting reversal of motor deficits. Graft-derived projections were observed in several brain areas, including, but not restricted to, normal target areas of striatal projection neurons. Transplantation also significantly reduced the secondary degeneration observed in the substantia nigra pars reticulata after disruption of the striato-nigral loop, suggesting a correlation with the presence of graft-derived fibers in the area. No teratoma, overgrowth, or reversal of neuronal commitment, were observed up to 5 months. These results show that hiPSCNPC bear similar potential than hESC-NPC for regenerative medicine in stroke and, at least partly, act by mechanisms related to integration of grafted cells into the host circuitry.

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