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<p>High doses of ionizing radiation (IR) cause severe damage to the hematopoietic system. However, the heterogeneity of hematopoietic stem and progenitor cells (HSPCs) in response to IR stress remains largely uncharacterized. Here, we present a dynamic single cell transcriptomic landscape and elucidate the complex crosstalk between HSPCs and the bone marrow (BM) microenvironment during IR-induced regeneration process. We reveal that BMP4 signaling in HSPCs confers IR resistance, and a single administration of BMP4 or SB4 can rescue mice from the IR-induced mortality. Furthermore, we identify BMPR2<sup>+</sup> HSCs as a radiation resistant subset, displaying distinct epigenetic landscapes from BMPR2<sup>−</sup> HSCs under radiation stress. BMPR2<sup>+</sup> HSCs sustain a strong self-renewal capacity primarily by reducing the H3K27me3 modification on the <i>Nrf2</i> gene in response to radiation stress. In <i>Nrf2</i> knockout mice, we demonstrate that <i>Nrf2</i> is a critical downstream functional gene for BMP4-BMPR2 signaling on HSCs to resist IR-induced damage. Collectively, we provide insights into the molecular intricacies underlying HSPC heterogeneity and BM niche after radiation exposure, and we uncover that BMP4-BMPR2 signaling may serve as a promising target for developing innovative and effective intervention strategies to mitigate IR-induced hematopoietic injury.</p>

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Single-cell transcriptomics reveals BMP4-BMPR2 signaling promotes radiation resistance in hematopoietic stem cells following injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Yanhua Li,
  • Yunxing Li,
  • Bowen Zhang,
  • Jiahui Zhao,
  • Jinhua Qin,
  • Siao Jiang,
  • Yunqiao Li,
  • Yanzhou Chen,
  • Jisheng Li,
  • Keyi Chen,
  • Yang Lv,
  • Tao Fan,
  • Zuyin Yu,
  • Hao Lu,
  • Cheng Quan,
  • Yiming Lu,
  • Xuetao Pei,
  • Gangqiao Zhou

摘要

High doses of ionizing radiation (IR) cause severe damage to the hematopoietic system. However, the heterogeneity of hematopoietic stem and progenitor cells (HSPCs) in response to IR stress remains largely uncharacterized. Here, we present a dynamic single cell transcriptomic landscape and elucidate the complex crosstalk between HSPCs and the bone marrow (BM) microenvironment during IR-induced regeneration process. We reveal that BMP4 signaling in HSPCs confers IR resistance, and a single administration of BMP4 or SB4 can rescue mice from the IR-induced mortality. Furthermore, we identify BMPR2+ HSCs as a radiation resistant subset, displaying distinct epigenetic landscapes from BMPR2− HSCs under radiation stress. BMPR2+ HSCs sustain a strong self-renewal capacity primarily by reducing the H3K27me3 modification on the Nrf2 gene in response to radiation stress. In Nrf2 knockout mice, we demonstrate that Nrf2 is a critical downstream functional gene for BMP4-BMPR2 signaling on HSCs to resist IR-induced damage. Collectively, we provide insights into the molecular intricacies underlying HSPC heterogeneity and BM niche after radiation exposure, and we uncover that BMP4-BMPR2 signaling may serve as a promising target for developing innovative and effective intervention strategies to mitigate IR-induced hematopoietic injury.