Mehatre Shubham Haribhau, Sanam Sreelakshmi, Agrawal Harsh, Hejjaji Amulya V, Kumar Akhila S, Alam Mohammad Tauqeer, Khurana Satish
School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala, 695551, India.
College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
EMBO J. 2025 Jun 5. doi: 10.1038/s44318-025-00477-2.
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.
脾脏是髓外造血的关键部位，其中存在少量功能性造血干细胞（HSC）。虽然支持髓外造血反应的微环境已引起关注，但稳态下脾脏HSC的生态位仍未得到描述。在这里，我们发现了一个红髓特异性的肌成纤维细胞生态位，它在一个约200μm宽的包膜区域内支持小鼠脾脏HSC。详细的空间分布和扰动分析表明，肌成纤维细胞在维持HSC处于静止状态方面具有重要作用。与成体骨髓的情况不同，脾脏生态位中的HSC在空间上与血管成分无关。粒细胞集落刺激因子（G-CSF）介导的趋化因子改变和5-氟尿嘧啶（5-FU）诱导的增殖导致HSC从脾脏包膜移位。有趣的是，恢复静止状态后，HSC重新占据靠近包膜肌成纤维细胞的生态位。蛋白质组相互作用组图谱证实了包膜肌成纤维细胞与脾脏HSC的相关性，并确定了HSC维持的潜在生态位调节因子。总之，这项研究证明了脾脏中HSC在稳态和应激状态下的动态定位及其生态位背景。它提供了一个模型来揭示对HSC功能至关重要的新型调节因子。
