The potential of motor cortical neurons derived hiPSC transplantation for brain repair following traumatic brain injury
Résumé
Traumatic brain injury (TBI) constitutes a leading public health concern, with limited treatment options available. Cell transplantation is a potential strategy to repair the injured brain. The recent discovery of human-induced pluripotent stem cells (hiPSC) offers an opportunity to generate patient-specific stem cells for cell-based replacement therapies. One highly clinically relevant cortical tissue in the context of cortical lesions is the motor cortex.
In this project, human IPSC were reprogrammed from dermal fibroblasts and then differentiated into three-dimensional aggregates of motor cortex progenitors. Our results showed at day 18 of differentiation, neurospheres displayed anterior fate, and still expressed neural stem cell marker (Nestin+). At day 46 of differentiation, cellular aggregates displayed motor cortical identity (CTIP2+, COUPTF1-), and expressed deep (CTIP2+, FoxP2+) and upper (CTIP2- and SATB2+) layers marker with layer V highly represented. In addition, neurospheres expressed neuronal (DCX, NeuN) and non-neuronal (GFAP+, Olig2+) markers.
In order to evaluate the therapeutic potential of motor cortical neurons derived hiPSC, D46-aggregates were grafted into the injured motor cortex. Two months after transplantation, the grafted cells expressed mainly the markers of immature neurons, and send projections to motor cortical targets not far from the transplant site such as the cortex and the striatum. Eight months after transplantation, the majority of grafted cells developed into mature neurons and expressed deep and upper cortical layer markers. Interestingly, the grafted neurons established specific point to point projections to the targets of motor cortex including the most distant targets such as the spinal cord. In addition, the grafted neurons established reciprocal synaptic connections with host neurons. Additional studies are underway to investigate the functionality of the transplanted neurons. These findings provide exciting evidences that hiPSC-derived motor cortical neurons could effectively re-establish the adult damaged motor cortical pathways.