Abstract
Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.
Highlights
Transcription factor-mediated reprogramming is currently the method of choice for the generation of induced pluripotent stem cells [1]
Murine fibroblasts have been converted into oligodendrocyte precursor cells (OPC) which in turn had the capacity to differentiate into myelinating oligodendrocytes when transplanted into the brain of a myelin-deficient mouse mutant [3,4]
We found that its overexpression in already Sox10-positive satellite glia of peripheral nervous system (PNS) dorsal root ganglia (DRG) is sufficient to generate oligodendrocyte-like cells in vivo
Summary
Transcription factor-mediated reprogramming is currently the method of choice for the generation of induced pluripotent stem (iPS) cells [1]. Successful conversion depends on the choice of transcription factors, but is influenced by the proteomic constitution of the targeted cell with some cells being more susceptible to acquiring a specific new identity than others [2] Both reprogramming and conversion are usually performed in culture with low efficiencies and are rarely studied in vivo. Murine fibroblasts have been converted into oligodendrocyte precursor cells (OPC) which in turn had the capacity to differentiate into myelinating oligodendrocytes when transplanted into the brain of a myelin-deficient mouse mutant [3,4] This feat is important as generation of oligodendroglial cells from iPS cells is relatively inefficient and time-consuming [5]. Once optimized and adopted to human cells, it offers a potential source for cell replacement strategies in the various demyelinating and dysmyelinating diseases
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