OCT4-induced oligodendrocyte progenitor cells promote remyelination and ameliorate disease

Abstract

The generation of human oligodendrocyte progenitor cells (OPCs) may be therapeutically valuable for human demyelinating diseases such as multiple sclerosis. Here, we report the direct reprogramming of human somatic cells into expandable induced OPCs (iOPCs) using a combination of OCT4 and a small molecule cocktail. This method enables generation of A2B5+ (an early marker for OPCs) iOPCs within 2 weeks retaining the ability to differentiate into MBP-positive mature oligodendrocytes. RNA-seq analysis revealed that the transcriptome of O4+ iOPCs was similar to that of O4+ OPCs and ChIP-seq analysis revealed that putative OCT4-binding regions were detected in the regulatory elements of CNS development-related genes. Notably, engrafted iOPCs remyelinated the brains of adult shiverer mice and experimental autoimmune encephalomyelitis mice with MOG-induced 14 weeks after transplantation. In conclusion, our study may contribute to the development of therapeutic approaches for neurological disorders, as well as facilitate the understanding of the molecular mechanisms underlying glial development.

Direct Conversion to Achieve Glial Cell Fates: Oligodendrocytes and Schwann Cells

“…Weider et al ( 76 ) reported that overexpression of SOX10 drives the cellular properties of peripheral satellite glia to resemble those of oligodendrocytes in vivo . Recent attempts to convert human fibroblasts into iOPCs has been also successful ( 77 ). Ectopic expression of OCT4, along with small molecules, directly converts human fibroblasts into expandable iOPCs.…”

“…Despite the great efforts aimed to successfully generate human iOPCs, the mechanism of the transcription factors used in the conversion process is still not clearly understood. Yun et al ( 77 ) employed OCT4 as a pioneer factor governing the opening of chromatin regions otherwise generally inaccessible in differentiated cells ( 78 , 79 ). In line with this, Dehghan et al ( 80 ) reported that the forced expression of OCT4 in combination with the administration of valproic acid to the demyelinated mouse brain enhanced myelin sheath repair, providing evidence for functional link between an OCT4 and the regulation of myelin related factors.…”

“…In line with this, Dehghan et al ( 80 ) reported that the forced expression of OCT4 in combination with the administration of valproic acid to the demyelinated mouse brain enhanced myelin sheath repair, providing evidence for functional link between an OCT4 and the regulation of myelin related factors. However, OCT4 alone-driven methods exhibit low efficiency in converting ratio of SOX10-expressing cells and induce uncharacterized heterogeneous populations ( 77 ). By contrast, the combined use of SOX10, OLIG2, and NKX6.2 strongly favored commitment to the specific OPC lineage from hPSCs-derived neural progenitor cells (differentiation) ( 46 ) and rodent fibroblasts (direct conversion) ( 70 , 81 ), suggesting that cell fate conversion to OPCs can be achieved with SOX10-combined methods in a more favorable manner.…”

“…Although direct conversion from cell types of the same lineage can be efficiently conducted, it is considered more feasible to utilize cell sources that are readily accessible. For example, direct conversion of human fibroblasts to OPCs and SCPs has been achieved ( 7 , 16 , 77 , 86 ). However, fibroblasts, in particular, are heterogenous and considered to have significant differences in properties depending on the anatomical locations and tissue types from which they are derived ( 93 - 95 ).…”

Using MS induced pluripotent stem cells to investigate MS aetiology

“…MS iPSCs may be an alternative source of disease relevant cell types that possess the full genetic component of MS risk from an individual with MS. iPSCs are ideally suited to studying the genetics of MS, however, the imprint of lifestyle and environmental factors, in the form of epigenetic modifications are lost during reprogramming (Kim et al, 2010). Epigenetic changes likely contribute to MS development and progression (Küçükali et al, 2015), but only direct reprogramming, which converts a mature cell type directly into another mature cell type, can preserve epigenetic signatures, and offer an alternative in vitro approach for studying the epigenetics of MS (Chanoumidou et al, 2021;Yun et al, 2022).…”