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<p>Neither rodent models nor in vitro studies of human cells adequately describe the molecular ontogeny of human glial progenitor cells (hGPCs). Here, we use scRNA-seq together with scATAC-Seq and CUT&amp;TAG assessment of chromatin accessibility to track the in vitro genesis and in vivo differentiation of hGPCs from pluripotent stem cells (PSCs). In vitro, the hGPC pool comprises 4 transcriptionally distinct subpopulations, each associated with a distinct pattern of chromatin accessibility and histone modification of stage-dependent genes. After the neonatal transplant of these cells into myelin-deficient shiverer mice (MBP<sup><i>shi/shi</i></sup>), they differentiate further as astrocytes and oligodendrocytes. A combination of gene co-expression, motif enrichment, cell-trajectory, cell-cell interaction, and spatial transcriptomic analyses reveals that the host environment potentiates the context-dependent differentiation of the hGPCs, via their activation of distinct gene regulatory networks. Together, these data describe the process and pathways by which human PSC-derived GPCs are generated in vitro and diversify in vivo to mature as astrocytes and oligodendrocytes.</p>

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Charting the transition from in vitro gliogenesis to the in vivo maturation of human glial progenitor cells transplanted into the hypomyelinated mouse brain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月23日

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  • John N. Mariani,
  • Steven J. Schanz,
  • Benjamin Mansky,
  • Xiaolu Wei,
  • Carter C. Long,
  • Devin Chandler-Militello,
  • Hannah E. Aichelman,
  • Nguyen P. T. Huynh,
  • Steven A. Goldman

摘要

Neither rodent models nor in vitro studies of human cells adequately describe the molecular ontogeny of human glial progenitor cells (hGPCs). Here, we use scRNA-seq together with scATAC-Seq and CUT&TAG assessment of chromatin accessibility to track the in vitro genesis and in vivo differentiation of hGPCs from pluripotent stem cells (PSCs). In vitro, the hGPC pool comprises 4 transcriptionally distinct subpopulations, each associated with a distinct pattern of chromatin accessibility and histone modification of stage-dependent genes. After the neonatal transplant of these cells into myelin-deficient shiverer mice (MBPshi/shi), they differentiate further as astrocytes and oligodendrocytes. A combination of gene co-expression, motif enrichment, cell-trajectory, cell-cell interaction, and spatial transcriptomic analyses reveals that the host environment potentiates the context-dependent differentiation of the hGPCs, via their activation of distinct gene regulatory networks. Together, these data describe the process and pathways by which human PSC-derived GPCs are generated in vitro and diversify in vivo to mature as astrocytes and oligodendrocytes.