Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, Republic of Korea.
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cell Stem Cell. 2021 Jul 1;28(7):1291-1306.e10. doi: 10.1016/j.stem.2021.02.023. Epub 2021 Apr 12.
Generation of induced oligodendrocyte progenitor cells (iOPCs) from somatic fibroblasts is a strategy for cell-based therapy of myelin diseases. However, iOPC generation is inefficient, and the resulting iOPCs exhibit limited expansion and differentiation competence. Here we overcome these limitations by transducing an optimized transcription factor combination into a permissive donor phenotype, the pericyte. Pericyte-derived iOPCs (PC-iOPCs) are stably expandable and functionally myelinogenic with high differentiation competence. Unexpectedly, however, we found that PC-iOPCs are metastable so that they can produce myelination-competent oligodendrocytes or revert to their original identity in a context-dependent fashion. Phenotypic reversion of PC-iOPCs is tightly linked to memory of their original transcriptome and epigenome. Phenotypic reversion can be disconnected from this donor cell memory effect, and in vivo myelination can eventually be achieved by transplantation of O4 pre-oligodendrocytes. Our data show that donor cell source and memory can contribute to the fate and stability of directly converted cells.
从体细胞核移植生成诱导性少突胶质前体细胞（iOPC）是髓鞘疾病细胞治疗的一种策略。然而，iOPC 的生成效率低下，且所得 iOPC 的扩增和分化能力有限。在此，我们通过将优化的转录因子组合转导到一个允许的供体表型——周细胞中，克服了这些限制。周细胞来源的 iOPC（PC-iOPC）具有稳定的扩增能力，且具有很高的分化能力，能够功能性髓鞘化。然而，出乎意料的是，我们发现 PC-iOPC 是亚稳定的，因此它们可以产生有髓鞘形成能力的少突胶质细胞，或以依赖于上下文的方式恢复其原始身份。PC-iOPC 的表型逆转与它们原始转录组和表观基因组的记忆紧密相关。表型逆转可以与这种供体细胞记忆效应脱钩，通过移植 O4 前少突胶质细胞最终可以实现体内髓鞘形成。我们的数据表明，供体细胞来源和记忆可能会影响直接转化细胞的命运和稳定性。
