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<p>Hematopoietic stem cells (HSC) sustain lifelong blood and immune system homeostasis. This study identifies P-selectin as a pivotal regulator of HSC function under aging and inflammatory stress. We observed pronounced <i>Selp</i> upregulation in aged HSC and inflammatory contexts, which drives excessive proliferation and differentiation while depleting their long-term self-renewal capacity. Using tissue-specific <i>Selp</i> overexpression models, we demonstrate that chronic <i>Selp</i> elevation disrupts HSC polarity, promotes oxidative stress accumulation, and induces genomic instability. Over time, sustained <i>Selp</i> expression leading to LT-HSC exhaustion and impaired hematopoietic reconstitution. Single-cell transcriptomics revealed that <i>Selp</i> enforces a pro-inflammatory transcriptional program in HSC, hyperactivating IFN-γ and PI3K-AKT-MOTR signaling pathways. Mechanistically, P-selectin directly interacted with IFNγR1 on the HSC surface, which driving activation of JAK1-STAT1 and PI3K-AKT-mTOR signaling axes. Notably, <i>Selp</i> overexpression suppresses the pathogenic capacity of leukemia stem cells (LSC), highlighting potential therapeutic implications. Our findings established P-selectin as a molecular nexus linking chronic inflammation and aging to hematopoietic decline, with dual therapeutic implications: targeting P-selectin may mitigate age-related hematopoietic dysfunction while offering a strategy to selectively impair LSC activity in malignancies.</p>

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P-selectin overexpression impairs hematopoietic stem cell homeostasis via inflammatory receptor-mediated proliferation and differentiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月21日

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  • Wei He,
  • Huandi Qiu,
  • Yunyu Feng,
  • Qiang Qiu,
  • Li Zheng,
  • Cong Pan,
  • Xue Cui,
  • Yuanyuan Sun,
  • Bochuan Wang,
  • Yiguo Hu

摘要

Hematopoietic stem cells (HSC) sustain lifelong blood and immune system homeostasis. This study identifies P-selectin as a pivotal regulator of HSC function under aging and inflammatory stress. We observed pronounced Selp upregulation in aged HSC and inflammatory contexts, which drives excessive proliferation and differentiation while depleting their long-term self-renewal capacity. Using tissue-specific Selp overexpression models, we demonstrate that chronic Selp elevation disrupts HSC polarity, promotes oxidative stress accumulation, and induces genomic instability. Over time, sustained Selp expression leading to LT-HSC exhaustion and impaired hematopoietic reconstitution. Single-cell transcriptomics revealed that Selp enforces a pro-inflammatory transcriptional program in HSC, hyperactivating IFN-γ and PI3K-AKT-MOTR signaling pathways. Mechanistically, P-selectin directly interacted with IFNγR1 on the HSC surface, which driving activation of JAK1-STAT1 and PI3K-AKT-mTOR signaling axes. Notably, Selp overexpression suppresses the pathogenic capacity of leukemia stem cells (LSC), highlighting potential therapeutic implications. Our findings established P-selectin as a molecular nexus linking chronic inflammation and aging to hematopoietic decline, with dual therapeutic implications: targeting P-selectin may mitigate age-related hematopoietic dysfunction while offering a strategy to selectively impair LSC activity in malignancies.