One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2

Summary Limited access to human oligodendrocytes impairs better understanding of oligodendrocyte pathology in myelin diseases. Here, we describe a method to robustly convert human fibroblasts directly into oligodendrocyte-like cells (dc-hiOLs), which allows evaluation of remyelination-promoting compounds and disease modeling. Ectopic expression of SOX10, OLIG2, and NKX6.2 in human fibroblasts results in rapid generation of O4+ cells, which further differentiate into MBP+ mature oligodendrocyte-like cells within 16 days. dc-hiOLs undergo chromatin remodeling to express oligodendrocyte markers, ensheath axons, and nanofibers in vitro, respond to promyelination compound treatment, and recapitulate in vitro oligodendroglial pathologies associated with Pelizaeus-Merzbacher leukodystrophy related to PLP1 mutations. Furthermore, DNA methylome analysis provides evidence that the CpG methylation pattern significantly differs between dc-hiOLs derived from fibroblasts of young and old donors, indicating the maintenance of the source cells’ “age.” In summary, dc-hiOLs represent a reproducible technology that could contribute to personalized medicine in the field of myelin diseases.
Graphical abstract
Highlights • SOX10, OLIG2, and NKX6.2 directly convert human fibroblasts into dc-hiOLs in 16 days • dc-hiOLs express key oligodendrocyte markers • dc-hiOLs preserve the epigenetic age of donor cells • dc-hiOLs from PMD patients show maturation deficit and vulnerability to cell death
In this article, Kuhlmann and colleagues show that human fibroblasts can be directly converted into oligodendrocyte-like cells (dc-hiOLs) upon overexpression of SOX10, OLIG2, and NKX6.2. dc-hiOLs undergo chromatin remodeling to activate oligodendrocyte-related genes, perform ensheathment in vitro, and maintain the epigenetic age of donor cells. The applicability of dc-hiOLs in promyelination compound screening and disease-modeling studies is demonstrated.