OCT4-induced oligodendrocyte progenitor cells promote remyelination and ameliorate disease

Wonjin Yun,Insik Hwang,Jeong Hee Kim,Gwonhwa Song,Wonji Choi,Minji Park,Ah-Young Jang,In Yong Kim,Jie Zheng,Wonjun Hong,Byung Sun Yoon,Ying Liu,Gyuman Park,Yong Jun Kim,Seungkwon You,Dae-Sung Kim,Sunghoi Hong,Kyung-Ah Choi

doi:10.1038/s41536-021-00199-z

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.

Highlights

The mammalian central nervous system (CNS) consists of a diverse array of cell types, including neurons, astrocytes, and oligodendrocytes, which mutually interact within the sophisticated structure and dynamics of neural networks
We hypothesized that human oligodendrocyte progenitor cells (OPCs) can be directly observed small round cells with a bipolar morphology consistent generated from fibroblasts in the presence of a combination of with OPCs in BJ and expression of GFP in SOX10::eGFP fibroblasts OCT4 and small molecules
Our findings clearly indicate that the ectopic expression of OCT4 in combination with small molecules, governing cell fate options and oligodendrocyte development such as A83–0144, thizovivin[45], VPA41. purmorphamine[6], and forskolin[24], allows the completion of the direct reprogramming of human fibroblasts into A2B5+ induced OPCs (iOPCs) expressing OLIG2 and SOX10 within two weeks (Fig. 7)

Summary

Introduction

The mammalian central nervous system (CNS) consists of a diverse array of cell types, including neurons, astrocytes, and oligodendrocytes, which mutually interact within the sophisticated structure and dynamics of neural networks. Substantial advances have been achieved in differentiating human pluripotent stem cells, including human embryonic stem cells (hESCs)[6,7,8] and induced pluripotent stem cells (iPSCs)[9,10,11] into OPCs. During the last decade, substantial advances have been achieved in differentiating human pluripotent stem cells, including human embryonic stem cells (hESCs)[6,7,8] and induced pluripotent stem cells (iPSCs)[9,10,11] into OPCs Notwithstanding their great achievements in the establishment of rapid, efficient, and highly reproducible protocol[12], these approaches require a longterm differentiation over three months. In this regard, several studies have been published on lineage-specific factor-driven generation of induced OPCs (iOPCs) from rodent fibroblasts[13,14] and human neural stem cells (NSCs)[15,16] within a period of three weeks. A combination of SOX10, OLIG2, and NKX6.2 (SON) was commonly used in both rodent and human[13,15], but the feasibility on applying these methods to human somatic cells remains uncertain

Methods

Results

Conclusion