Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221002, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou 221002, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; Xuzhou Ruihu Health Management Consulting Co., Ltd, Xuzhou 221002, China.
Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221002, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou 221002, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
Int Immunopharmacol. 2024 Mar 30;130:111760. doi: 10.1016/j.intimp.2024.111760. Epub 2024 Feb 29.
Bone marrow macrophages (Mφ) are essential components of the bone marrow niche that regulate the function of hematopoietic stem cells. Poor graft function and inhibition of hematopoietic production can result from abnormal macrophage function; however, the underlying mechanism is unclear. Clodronate liposomes (Clo-Lip) have been used widely to deplete macrophages and study their functions. Our previous results showed that Clod-Lip-mediated clearance of macrophages plays a vital role in regulating hematopoietic reconstruction after allogeneic hematopoietic cell transplantation (HCT). In this study, using an isogenic hematopoietic stem cell transplantation model, we found that Clod-Lip-mediated clearance of macrophages suppressed hematopoietic reconstruction by inhibiting the homing process of hematopoietic cells. We also demonstrated that macrophage depletion inhibited the direct supportive effect of macrophages on hematopoietic stem and progenitor cells and erythroid differentiation but promoted the production of megakaryocytic progenitors ex vivo. We showed that macrophages increase CD49e expression on hematopoietic stem and progenitor cells (HSPCs). However, CD49e inhibitors did not support the proliferative effect of macrophages on hematopoietic cells. In contrast, macrophage E-selectin/ intercellular cell adhesion molecule-1 (ICAM-1) may be involved in directly regulating HSPCs. In conclusion, macrophage depletion with Clo-Lip partially disrupts bone marrow hematopoiesis after HCT by impeding donor cell homing and macrophage-HSPCs interactions.
骨髓巨噬细胞（Mφ）是骨髓龛的重要组成部分，调节造血干细胞的功能。巨噬细胞功能异常可导致移植物功能不良和造血生成抑制；然而，其潜在机制尚不清楚。氯膦酸脂质体（Clo-Lip）已被广泛用于耗尽巨噬细胞并研究其功能。我们之前的结果表明，Clo-Lip 介导的巨噬细胞清除在同种异体造血细胞移植（HCT）后造血重建中起着至关重要的作用。在这项研究中，我们使用同基因造血干细胞移植模型发现，Clo-Lip 介导的巨噬细胞清除通过抑制造血细胞的归巢过程抑制造血重建。我们还证明，巨噬细胞耗竭抑制了巨噬细胞对造血干细胞和祖细胞以及红细胞分化的直接支持作用，但促进了巨核细胞祖细胞的体外产生。我们表明巨噬细胞增加了造血干细胞和祖细胞（HSPCs）上的 CD49e 表达。然而，CD49e 抑制剂不能支持巨噬细胞对造血细胞的增殖作用。相反，巨噬细胞 E-选择素/细胞间黏附分子-1（ICAM-1）可能参与直接调节 HSPCs。总之，Clo-Lip 耗尽巨噬细胞通过阻碍供体细胞归巢和巨噬细胞-HSPCs 相互作用，部分破坏 HCT 后的骨髓造血。
