Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.

IF 17 Q1 CELL BIOLOGY
Nature aging Pub Date : 2025-04-01 Epub Date: 2025-01-29 DOI:10.1038/s43587-024-00798-7
Dorsa Toghani, Sanika Gupte, Sharon Zeng, Elmir Mahammadov, Edie I Crosse, Negar Seyedhassantehrani, Christian Burns, David Gravano, Stefan Radtke, Hans-Peter Kiem, Sonia Rodriguez, Nadia Carlesso, Amogh Pradeep, Alexis Georgiades, Fabienne Lucas, Nicola K Wilson, Sarah J Kinston, Berthold Göttgens, Le Zong, Isabel Beerman, Bongsoo Park, Derek H Janssens, Daniel Jones, Ali Toghani, Claus Nerlov, Eric M Pietras, Marion Mesnieres, Christa Maes, Atsushi Kumanogoh, Thomas Worzfeld, Jin-Gyu Cheong, Steven Z Josefowicz, Peter Kharchenko, David T Scadden, Antonio Scialdone, Joel A Spencer, Lev Silberstein
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引用次数: 0

Abstract

Somatic stem cell pools comprise diverse, highly specialized subsets whose individual contribution is critical for the overall regenerative function. In the bone marrow, myeloid-biased hematopoietic stem cells (myHSCs) are indispensable for replenishment of myeloid cells and platelets during inflammatory response but, at the same time, become irreversibly damaged during inflammation and aging. Here we identify an extrinsic factor, Semaphorin 4A (Sema4A), which non-cell-autonomously confers myHSC resilience to inflammatory stress. We show that, in the absence of Sema4A, myHSC inflammatory hyper-responsiveness in young mice drives excessive myHSC expansion, myeloid bias and profound loss of regenerative function with age. Mechanistically, Sema4A is mainly produced by neutrophils, signals via a cell surface receptor, Plexin D1, and safeguards the myHSC epigenetic state. Our study shows that, by selectively protecting a distinct stem cell subset, an extrinsic factor preserves functional diversity of somatic stem cell pool throughout organismal lifespan.

小生境衍生的信号蛋白4A保护骨髓偏向性造血干细胞的功能特性。
体细胞干细胞库包括多种多样、高度特化的亚群,其个体贡献对整体再生功能至关重要。在骨髓中,骨髓偏向性造血干细胞(myhsc)在炎症反应中对骨髓细胞和血小板的补充是必不可少的,但同时,在炎症和衰老过程中,myhsc会受到不可逆转的损伤。在这里,我们确定了一个外在因素,信号蛋白4A (Sema4A),它非细胞自主地赋予myHSC对炎症应激的恢复能力。我们发现,在缺乏Sema4A的情况下,年轻小鼠的myHSC炎症高反应性会导致myHSC过度扩张、骨髓偏态和随着年龄增长而严重丧失再生功能。从机制上讲,Sema4A主要由中性粒细胞产生,通过细胞表面受体丛蛋白D1发出信号,并保护myHSC的表观遗传状态。我们的研究表明,通过选择性地保护一个独特的干细胞亚群,一个外在因素在整个生物体生命周期中保持了体细胞干细胞库的功能多样性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
14.70
自引率
0.00%
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