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<p>The spleen is a key site for extramedullary hematopoiesis that hosts a rare population of functional hematopoietic stem cells (HSCs). While the microenvironment that supports extramedullary hematopoiesis response has gained interest, a niche for splenic HSCs at steady-state remains undescribed. Here, we have uncovered a red-pulp-specific, myofibroblastic niche that supports murine splenic HSCs within a ≈ 200-μm-wide capsular zone. Detailed spatial-distribution and perturbation analysis showed the importance of myofibroblasts in maintaining HSCs in a quiescent state. Unlike reported for the adult bone marrow, the HSCs in splenic niche were not spatially associated with vascular components. G-CSF-mediated chemokine alteration and 5-FU-induced proliferation resulted in HSCs shifts away from the splenic capsule. Interestingly, upon regaining quiescence, the HSCs re-occupied niches close to capsular myofibroblasts. Proteomic interactome profiles confirmed the relevance of capsular myofibroblasts for splenic HSCs and identified potential niche regulators of HSC maintenance. Together, this study demonstrates a dynamic HSC localization in the spleen and its niche context at homeostasis and under stress. It offers a model to uncover novel regulators crucial for HSC function.</p>

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A capsular myofibroblastic niche maintains hematopoietic stem cells in the spleen

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月5日

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  • Shubham Haribhau Mehatre,
  • Sreelakshmi Sanam,
  • Harsh Agrawal,
  • Amulya V Hejjaji,
  • Akhila S Kumar,
  • Mohammad Tauqeer Alam,
  • Satish Khurana

摘要

The spleen is a key site for extramedullary hematopoiesis that hosts a rare population of functional hematopoietic stem cells (HSCs). While the microenvironment that supports extramedullary hematopoiesis response has gained interest, a niche for splenic HSCs at steady-state remains undescribed. Here, we have uncovered a red-pulp-specific, myofibroblastic niche that supports murine splenic HSCs within a ≈ 200-μm-wide capsular zone. Detailed spatial-distribution and perturbation analysis showed the importance of myofibroblasts in maintaining HSCs in a quiescent state. Unlike reported for the adult bone marrow, the HSCs in splenic niche were not spatially associated with vascular components. G-CSF-mediated chemokine alteration and 5-FU-induced proliferation resulted in HSCs shifts away from the splenic capsule. Interestingly, upon regaining quiescence, the HSCs re-occupied niches close to capsular myofibroblasts. Proteomic interactome profiles confirmed the relevance of capsular myofibroblasts for splenic HSCs and identified potential niche regulators of HSC maintenance. Together, this study demonstrates a dynamic HSC localization in the spleen and its niche context at homeostasis and under stress. It offers a model to uncover novel regulators crucial for HSC function.