Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF– or inflammation-induced stress myelopoiesis. Del-1–induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

中文翻译：

---

分泌蛋白Del-1调节造血干细胞生态位中的骨髓生成

造血干细胞（HSC）在稳态条件下大部分保持静止，但在造血应激（例如，骨髓（BM）损伤，移植或全身感染和炎症）后转变为增殖状态。HSC的静止，自我更新和分化之间的稳态平衡在很大程度上取决于它们与构成BM中称为HSC生态位的特殊微解剖环境的细胞之间的相互作用。在这里，我们确定分泌的细胞外基质蛋白Del-1是HSC生态位的组成部分和调节因子。具体来说，我们发现Del-1是由HSC生态位的几个细胞成分表达的，包括小动脉内皮细胞，CXCL12丰富的网状（CAR）细胞和成骨细胞系的细胞。Del-1促进了HSC细分市场的关键功能，因为它调节了长期HSC（LT-HSC）向骨髓谱系的增殖和分化。小鼠中的Del-1缺乏症导致LT-HSC增殖减少，并在稳态和应激条件（例如造血细胞移植和G-CSF-或炎症诱导的应激骨髓生成）中优先侵犯了骨髓生成。β1整合素对造血祖细胞介导Del-1诱导的HSC增殖和髓系沿袭。在HSC领域中迄今未知的Del-1功能代表在应激性骨髓生成过程中造血系统的顺他克林稳态适应。小鼠中的Del-1缺乏症导致LT-HSC增殖减少，并在稳态和应激条件（例如造血细胞移植和G-CSF-或炎症诱导的应激骨髓生成）中优先侵犯了骨髓生成。β1整合素对造血祖细胞介导Del-1诱导的HSC增殖和髓系沿袭。在HSC领域中迄今未知的Del-1功能代表在应激性骨髓生成过程中造血系统的顺他克林稳态适应。小鼠中的Del-1缺乏症导致LT-HSC增殖减少，并在稳态和应激条件（例如造血细胞移植和G-CSF-或炎症诱导的应激骨髓生成）中优先侵犯了骨髓生成。β1整合素对造血祖细胞介导Del-1诱导的HSC增殖和髓系沿袭。在HSC领域中迄今未知的Del-1功能代表在应激性骨髓生成过程中造血系统的顺他克林稳态适应。