Single-Cell Transcriptomic Analysis Reveals Molecular Diversity of Human Oligodendrocyte Progenitor Cells

Author:

Chamling XitizORCID,Kallman Alyssa,Berlinicke Cindy,Devkota Prajwal,Mertz Joseph L.ORCID,Chang Calvin,Kaushik Aniruddha,Chen Liben,Calabresi Peter A.,Mao Hai-Quan,Wang Tza-Huei,Zack Donald J.ORCID

Abstract

ABSTRACTInjury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, we performed single-cell-transcriptomic-analysis of developing human oligodendrocyte-precursor-cells (hOPCs). We engineered knock-in hESC-reporter lines in which an Identification-and-Purification tag is expressed under control of the endogenous, OPC-specific, PDGFRα promoter, and performed time-course single-cell-RNA-sequencing of purified hOPCs. Our analysis uncovered marked transcriptional heterogeneity of PDGFRα+ hOPCs and identified regulatory genes and networks that control their differentiation and myelination competence. Pseudotime trajectory analysis revealed two distinct trajectories for the development of oligodendrocytes vs astrocytes from hOPCs. We also identified novel transcription factors and other genes that developing hOPCs potentially use to choose between oligodendrocyte vs astrocyte lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of those pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs.

Publisher

Cold Spring Harbor Laboratory

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