Competition between hematopoietic stem and progenitor cells controls the hematopoietic stem cell homeostasis [bulk RNA-seq]

Cellular competition for limiting hematopoietic factors is a physiologically regulated but poorly understood process. Here, we studied this phenomenon by hampering hematopoietic progenitor access to Leptin receptor+ mesenchymal stem/progenitor cells (MSPCs) and endothelial cells (ECs). We showed that HSC numbers increased by 2-fold when multipotent and lineage-restricted progenitors fail to respond to CXCL12 produced by MSPCs and ECs. HSCs were qualitatively normal, and HSC expansion only occurred when early hematopoietic progenitors but not differentiated hematopoietic cells lacked CXCR4. Furthermore, the MSPC and EC transcriptomic heterogeneity was remarkably stable, suggesting that it is impervious to dramatic changes in hematopoietic progenitor interactions. Instead, HSC expansion was caused by increased availability of membrane-bound stem cell factor (mSCF) on MSPCs and ECs due to reduced consumption by cKit-expressing hematopoietic progenitors. These studies revealed an intricate homeostatic balance between HSCs and proximal hematopoietic progenitors regulated by cell competition for limiting amounts of mSCF.针对有限造血因子的细胞竞争是一种受生理调控但机制尚不明确的生理过程。本研究通过阻断造血祖细胞与瘦素受体阳性（Leptin receptor+）间充质干细胞/祖细胞（MSPCs）及内皮细胞（ECs）的相互作用，对该现象展开系统性探究。研究发现，当多能造血祖细胞及谱系限制性祖细胞无法响应MSPCs与ECs分泌的CXC趋化因子配体12（CXCL12）时，造血干细胞（Hematopoietic Stem Cell, HSC）的数量可增至原本的2倍。此类造血干细胞功能未见异常，且仅在早期造血祖细胞（而非分化型造血细胞）缺乏CXC趋化因子受体4（CXCR4）的情况下，才会出现造血干细胞扩增现象。进一步分析显示，MSPCs与ECs的转录组异质性保持显著稳定，表明其不受造血祖细胞相互作用剧烈变化的影响。相反，造血干细胞扩增的诱因在于：表达c-Kit的造血祖细胞对膜结合型干细胞因子（membrane-bound stem cell factor, mSCF）的消耗减少，使得MSPCs与ECs表面的mSCF可获得性显著提升。本研究揭示了造血干细胞与邻近造血祖细胞之间存在一套复杂的稳态平衡机制，该机制由细胞针对有限量mSCF的竞争行为所调控。