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Differentiation of Fibroblast-Derived Induced Pluripotent Cells into Oligodendrocytes for Treatment of Neurological Disorders
Spinal cord injury is a devastating condition, which imposes major individual and societal costs. The goal of our work is to promote functional recovery in patients following spinal cord injury by utilizing therapeutic approaches that promote remyelination. Remyelination from the transplanted cells is one mechanism that can induce partial functional recovery.
In a rodent model of SCI, transplanted human embryonic stem cells (hESC)‐derived oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes (OLs), and go on to myelinate spared axons. However, significant ethical and safety concerns remain associated with the use of hESCs in a clinical setting; these include the possibility of immune rejection, and the need for immunosuppression in a patient population that is at risk of lifethreatening infections. The generation of induced pluripotent stem cells (iPSCs) is delivering on the promise of creating patient‐specific cells for therapeutic transplantations. Unlike, hESCs, the use of iPSCs in transplantation‐based therapeutic approaches does not face any immune related issues or ethical ones. The differentiation potential of human iPSCs has been shown by their direct differentiation into neural progenitor cells, mature neurons, cardiomyocytes, insulin‐producing pancreatic cells, and hepatocytes.
Here, we will initially characterize the differentiation potential of human iPSC‐derived cells by expression of OL lineage markers (A2B5, OPCs; O4, premyelinating OL; RIP, mature OLs); and myelination potential by measuring the co‐localization of MBP and neurofilament in neuronal and OPC co‐cultures. We will then generate gene expression profiles for enriched iPSC‐derived OPCs and OLs and compare them with cells generated from hESC that are at the same stage of differentiation (OPC and mature OL). This novel data will:
- Provide us with insights into the signaling pathways involved in driving the differentiation of human iPSCs and hESCs toward the OLs lineage
- It represents a potential quality control procedure for assessing the quality of iPSC‐derived OPCs prior to transplantation.
We will also test the ability of iPSC‐derived OPCs to induce functional recovery following transplantation in a clinically relevant model of contusive SCI. The measured functional improvements will be correlated to the myelination of the sparred spinal cord axons, specifically the rubrospinal tract (RST, heavily myelinated tract involved in motor function).