Generation of oligodendroglial cells by direct lineage conversion

Abstract

Transplantation of oligodendrocyte precursor cells (OPCs) is a promising potential therapeutic strategy for diseases affecting myelin. However, the derivation of engraftable OPCs from human pluripotent stem cells has proven difficult and primary OPCs are not readily available. Here we report the generation of induced OPCs (iOPCs) by direct lineage conversion. Forced expression of the three transcription factors Sox10, Olig2 and Zfp536 was sufficient to reprogram mouse and rat fibroblasts into iOPCs with morphologies and gene expression signatures resembling primary OPCs. More importantly, iOPCs gave rise to mature oligodendrocytes that could ensheath multiple host axons when co-cultured with primary dorsal root ganglion cells and formed myelin after transplantion into shiverer mice. We propose direct lineage reprogramming as a viable alternative approach for the generation of OPCs for use in disease modeling and regenerative medicine.

5. Themenbereich Stammzellen: Aktuelle Entwicklungen der Stammzellforschung in Deutschland

“…Dabei reicht ein Cocktail von drei Faktoren (Ascl1, Brn2 (Pou3f2) und Myt1l), um Fibroblasten in vitro effizient und schnell in funktionelle Neurone zu konvertieren (Vierbuchen et al, 2010). Spätere Arbeiten derselben Gruppe belegen die Erzeugung oligodendroglialer 34 Vorläuferzel-len (OPC) durch direkte Reprogrammierung (Yang et al, 2013). Diese Zellen werden als interessante Vorläuferzellen zur Therapie myeliner Erkrankungen beschrieben.…”

Lineage-reprogramming of Pericyte-derived Cells of the Adult Human Brain into Induced Neurons

“…It remains to be tested whether the factor combinations used in fibroblasts induce the same transmitter identity in PdiNs. Moreover, recent work has expanded the conversion spectrum beyond neurogenesis to generate neural stem cells 19,20 or glial, in particular oligodendrocytes 21,22 . If these reprogramming protocols elicit a similar outcome in adult human brain pericyte-derived cells, this would greatly widen the panorama of applications of this important brain-resident cell type.…”

Review: Direct conversion in Neuro-regenerative Medicine

“…After screening of the eight selected transcription factors, three of them (Sox10, Olig2 and Nkx 6.2) turned out to be sufficient to generate iOPCs [8]. Another group, Yang, N et al, showed that a different combination of three transcription factors (Sox10, Olig2, and Zfp536) converted mouse fibroblast to iOPCs [9]. To verify the functionality of iOPCs, they were transplanted into disease model mice.…”

“…To verify the functionality of iOPCs, they were transplanted into disease model mice. 12 weeks after injection, it was demonstrated that iOPCs can differentiate into myelinogenic oligodendrocytes expressing oligodendrocyte markers as well as dense myelin sheaths [9].…”