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Differentiation of Fibroblast-Derived Induced Pluripotent Cells into Oligodendrocytes for Treatment of Neurological Disorders
The isolation of human embryonic stem cells (hSECs) and the development of protocols to differentiate these cells toward various lineages are revolutionizing regenerative medicine. Transplantation of these cells has shown promise towards the treatment of nervous system disorders, particularly spinal cord injury (SCI). In a clinically relevant rodent model of SCI, transplantation of hESC-derived oligodendrocytes precursors cells (OPCs) induces partial recovery of complex motor functions.
Efforts to apply such a therapeutic approach in humans are complicated by the possibility of immune rejection due to the immunological incompatibility between the patient and the transplanted cells. The generation of fibroblast-derived induced pluripotent stem cells (iPSCs) eliminates this issue by allowing the creation of patient-specific cell lines. Differentiation protocols developed for directing hESCs into cells of central nervous system (CNS) have also been utilized to direct the differentiation of human iPSCs toward CNS cell lineages, to date mainly neural progenitors and neurons. Transplantation of iPSC-derived neural progenitors has been shown to induce functional recovery in a rodent SCI model as well, and some of the transplanted cells differentiate into mature OLs, and myelinate surviving axons. However, transplantation of these cells also results in tumor formation, and safe use of human iPSC-derived neural progenitors requires an additional purification step to remove potentially undifferentiated cells prior to transplantation.
The novelty of this exploratory application consists of the generation of human iPSC-derived OPCs, the use of these cells for treatment of SCI, and detailed characterization of differentiated human iPSC-derived OPCs and their myelination potential. We will test the hypothesis that long-term survival, differentiation into mature OLs, and track specific myelination of spared axons by the transplanted iPSC-derived OPCs is required for functional recovery in a clinically relevant rodent model of SCI.