Direct reprogramming of mouse embryonic fibroblasts to oligodendrocyte progenitor cells using various transcription factors

Abstract

Spinal cord injury (SCI) is a debilitating disorder that affects numerous aspects of a person's health. After injury, oligodendrocytes (myelinating glial cells) in the damaged spinal cord undergo cell death leading to additional loss of function. Transplantation of oligodendrocyte progenitor cells (OPCs) into injured spinal cords has been shown to increase myelination of axons and improve function in animal models of SCI. Differentiation of human embryonic stem cells (ESCs) and induced pluripotent stem cells (IPSCs) has been proposed to generate OPCs for clinical use. However, using hESCs poses ethical issues and IPSC methods take many weeks to produce OPCs. Various groups have proposed that using direct reprogramming will create a faster method for producing OPCs. Using combinations of transcription factors it was initially found that co-expression of exogenous FoxG1, Sox2, and Brn2 in embryonic fibroblasts can produce a tripotent neural cell lineage that gives rise to neurons and glial cells including oligodendrocytes. It was also shown that FoxG1 and Brn2 alone could produce OPCs. Following these findings it was shown that one transcription factor, Sox2 could produce induced neural stem cells that could differentiate into glial cell types. In this project we attempted to create a population of OPCs using these transcription factors by direct reprogramming of Olig2:CreER mT/mG transgenic mouse embryonic fibroblasts.