Myeloid-biased HSC require Semaphorin 4A from the bone marrow niche for self-renewal under stress and life-long persistence

Tissue stem cells are hierarchically organized. Those that are most primitive serve as key drivers of regenerative response but the signals that selectively preserve their functional integrity are largely unknown. Here, we identify a secreted factor, Semaphorin 4A (Sema4A), as a specific regulator of myeloid-biased hematopoietic stem cells (myHSC), which are positioned at the top of the HSC hierarchy. Lack of Sema4A leads to exaggerated myHSC (but not downstream “balanced” HSC) proliferation after acute inflammatory stress, indicating that Sema4A enforces myHSC quiescence. Strikingly, aged Sema4A knock-out myHSC expand but almost completely lose reconstitution capacity. The effect of Sema4A is non cell-autonomous, since upon transplantation into Sema4A-deficient environment, wild-type myHSC excessively proliferate but fail to engraft long-term. Sema4A constrains inflammatory signaling in myHSC and acts via a surface receptor Plexin-D1. Our data support a model whereby the most primitive tissue stem cells critically rely on a dedicated signal from the niche for self-renewal and life-long persistence. Overall design: ATAC sequencig were performed to compare the epigenome between Sema4aKO myHSCs and WT myHSCs.

组织干细胞（tissue stem cells）呈层级结构排布。其中最为原始的干细胞群体是再生应答的核心驱动因素，但目前学界对其功能完整性的选择性维持信号仍知之甚少。本研究鉴定出一种分泌因子——信号素4A（Semaphorin 4A, Sema4A），作为定位于造血干细胞（hematopoietic stem cell, HSC）层级顶端的髓系偏倚造血干细胞（myeloid-biased hematopoietic stem cells, myHSC）的特异性调控因子。在急性炎症应激条件下，Sema4A缺失会导致myHSC过度增殖（但不影响下游的“平衡型”造血干细胞），这表明Sema4A可维持myHSC的静息状态。值得注意的是，衰老的Sema4A敲除型myHSC虽会发生扩增，但几乎完全丧失了造血重建能力。Sema4A的调控作用并非细胞自主的：当将野生型myHSC移植至Sema4A缺陷的微环境（niche）中时，其会发生过度增殖，但无法实现长期植入。Sema4A可抑制myHSC内的炎症信号通路，并通过表面受体Plexin-D1发挥调控作用。本研究数据支持如下模型：最为原始的组织干细胞严重依赖于微环境（niche）发出的特异性信号，以实现自我更新与终身存续。实验整体设计：通过ATAC测序（ATAC sequencing）比较Sema4A敲除型myHSC与野生型myHSC的表观基因组差异。