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<p>Human pluripotent stem cells (hPSCs) can in theory give rise to any hematopoietic lineages, thereby offering opportunities for disease modeling, drug screening and cell therapies. However, gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells (HSPCs), which lie at the apex of all hematopoietic lineages, greatly limit the potential of hPSC in hematological research and application. Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells (hPSC-HPCs), which results in higher mitochondria activity, misregulation of <i>HOX</i> genes, loss of self-renewal and precocious differentiation. These defects are partly due to the activation of the WNT target gene <i>CDX2</i>. Late-stage WNT inhibition improves the yield, self-renewal, multilineage differentiation, and transcriptional and metabolic profiles of hPSC-HPCs. Genome-wide mapping of transcription factor (TF) accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs, which could underlie their myeloid-biased lineage potential. Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs. Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells (HSCs), thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.</p>

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Dynamic WNT signaling controls differentiation of hematopoietic progenitor cells from human pluripotent stem cells

  • 期刊论文

  • 发表日期：

    2025年3月11日

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  • Mo Li,
  • Keiichiro Suzuki,
  • Mengge Wang,
  • Christopher Benner,
  • Manching Ku,
  • Li Ma,
  • Ladan Kobari,
  • Na Young Kim,
  • Nuria Montserrat,
  • Chan-Jung Chang,
  • Guanghui Liu,
  • Jing Qu,
  • Jinna Xu,
  • Yingzi Zhang,
  • Emi Aizawa,
  • Jun Wu,
  • Luc Douay,
  • Concepcion Rodriguez Esteban,
  • Juan Carlos Izpisua Belmonte

摘要

Human pluripotent stem cells (hPSCs) can in theory give rise to any hematopoietic lineages, thereby offering opportunities for disease modeling, drug screening and cell therapies. However, gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells (HSPCs), which lie at the apex of all hematopoietic lineages, greatly limit the potential of hPSC in hematological research and application. Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells (hPSC-HPCs), which results in higher mitochondria activity, misregulation of HOX genes, loss of self-renewal and precocious differentiation. These defects are partly due to the activation of the WNT target gene CDX2. Late-stage WNT inhibition improves the yield, self-renewal, multilineage differentiation, and transcriptional and metabolic profiles of hPSC-HPCs. Genome-wide mapping of transcription factor (TF) accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs, which could underlie their myeloid-biased lineage potential. Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs. Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells (HSCs), thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.