Single-cell transcriptomic reveals molecular diversity and developmental heterogeneity of human stem cell-derived oligodendrocyte lineage cells

Xitiz Chamling, Alyssa Kallman, Weixiang Fang, Cynthia A. Berlinicke, Joseph L. Mertz, Prajwal Devkota, Itzy E. Morales Pantoja, Matthew D. Smith, Zhicheng Ji, Calvin Chang, Aniruddha Kaushik, Liben Chen, Katharine A. Whartenby, Peter A. Calabresi, Hai-Quan Mao, Hongkai Ji, Tza-Huei Wang and Donald J. Zack ()
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Xitiz Chamling: Johns Hopkins University School of Medicine
Alyssa Kallman: Johns Hopkins University School of Medicine
Weixiang Fang: Johns Hopkins Bloomberg School of Public Health
Cynthia A. Berlinicke: Johns Hopkins University School of Medicine
Joseph L. Mertz: Johns Hopkins University School of Medicine
Prajwal Devkota: University of Miami
Itzy E. Morales Pantoja: Johns Hopkins University School of Medicine
Matthew D. Smith: Johns Hopkins University School of Medicine
Zhicheng Ji: Johns Hopkins Bloomberg School of Public Health
Calvin Chang: Johns Hopkins School of Medicine
Aniruddha Kaushik: Johns Hopkins University
Liben Chen: Johns Hopkins University
Katharine A. Whartenby: Johns Hopkins University School of Medicine
Peter A. Calabresi: Johns Hopkins University School of Medicine
Hai-Quan Mao: Johns Hopkins School of Medicine
Hongkai Ji: Johns Hopkins Bloomberg School of Public Health
Tza-Huei Wang: Johns Hopkins School of Medicine
Donald J. Zack: Johns Hopkins University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Injury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of human oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, here we describe time-course single-cell-transcriptomic analysis of developing human stem cell-derived oligodendrocyte-lineage-cells (hOLLCs). The study includes hOLLCs derived from both genome engineered embryonic stem cell (ESC) reporter cells containing an Identification-and-Purification tag driven by the endogenous PDGFRα promoter and from unmodified induced pluripotent (iPS) cells. Our analysis uncovers substantial transcriptional heterogeneity of PDGFRα-lineage hOLLCs. We discover sub-populations of human oligodendrocyte progenitor cells (hOPCs) including a potential cytokine-responsive hOPC subset, and identify candidate regulatory genes/networks that define the identity of these sub-populations. Pseudotime trajectory analysis defines developmental pathways of oligodendrocytes vs astrocytes from PDGFRα-expressing hOPCs and predicts differentially expressed genes between the two lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of these pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs.

Date: 2021
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DOI: 10.1038/s41467-021-20892-3

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