Mitroulis Ioannis, Chen Lan-Sun, Singh Rashim Pal, Kourtzelis Ioannis, Economopoulou Matina, Kajikawa Tetsuhiro, Troullinaki Maria, Ziogas Athanasios, Ruppova Klara, Hosur Kavita, Maekawa Tomoki, Wang Baomei, Subramanian Pallavi, Tonn Torsten, Verginis Panayotis, von Bonin Malte, Wobus Manja, Bornhäuser Martin, Grinenko Tatyana, Di Scala Marianna, Hidalgo Andres, Wielockx Ben, Hajishengallis George, Chavakis Triantafyllos
Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, and.
Department of Ophthalmology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
J Clin Invest. 2017 Oct 2;127(10):3624-3639. doi: 10.1172/JCI92571. Epub 2017 Aug 28.
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.
造血干细胞（HSCs）在稳态条件下大多处于静止状态，但在造血应激后会转变为增殖状态，例如骨髓（BM）损伤、移植或全身性感染及炎症。造血干细胞静止、自我更新和分化之间的稳态平衡强烈依赖于它们与构成骨髓中一个特殊微解剖环境（即造血干细胞龛）的细胞之间的相互作用。在此，我们鉴定出分泌型细胞外基质蛋白Del-1是造血干细胞龛的一个组成部分和调节因子。具体而言，我们发现Del-1由造血干细胞龛的几种细胞成分表达，包括小动脉内皮细胞、富含CXCL12的网状（CAR）细胞和成骨细胞系细胞。Del-1促进造血干细胞龛的关键功能，因为它调节长期造血干细胞（LT-HSCs）的增殖以及向髓系谱系的分化。小鼠中Del-1的缺失导致LT-HSC增殖减少，并且在稳态和应激条件下（如造血细胞移植以及G-CSF或炎症诱导的应激性骨髓生成）优先影响髓系造血。Del-1诱导的造血干细胞增殖和髓系谱系定向由造血祖细胞上的β3整合素介导。造血干细胞龛中这种迄今未知的Del-1功能代表了应激性骨髓生成中造血系统的一种旁分泌稳态适应。
