Department of Medicine, Division of Molecular Medicine, Columbia University, New York, NY 10032, USA.
Cell Stem Cell. 2012 Aug 3;11(2):195-206. doi: 10.1016/j.stem.2012.04.024.
Intact cholesterol homeostasis helps to maintain hematopoietic stem and multipotential progenitor cell (HSPC) quiescence. Mice with defects in cholesterol efflux pathways due to deficiencies of the ATP binding cassette transporters ABCA1 and ABCG1 displayed a dramatic increase in HSPC mobilization and extramedullary hematopoiesis. Increased extramedullary hematopoiesis was associated with elevated serum levels of G-CSF due to generation of IL-23 by splenic macrophages and dendritic cells. This favored hematopoietic lineage decisions toward granulocytes rather than macrophages in the bone marrow leading to impaired support for osteoblasts and decreased Cxcl12/SDF-1 production by mesenchymal progenitors. Greater HSPC mobilization and extramedullary hematopoiesis were reversed by raising HDL levels in Abca1(-/-)Abcg1(-/-) and Apoe(-/-) mice or in a mouse model of myeloproliferative neoplasm mediated by Flt3-ITD mutation. Our data identify a role of cholesterol efflux pathways in the control of HSPC mobilization. This may translate into therapeutic strategies for atherosclerosis and hematologic malignancies.
完整的胆固醇稳态有助于维持造血干细胞和多能祖细胞（HSPC）的静止状态。由于 ATP 结合盒转运蛋白 ABCA1 和 ABCG1 的缺陷导致胆固醇外排途径缺陷的小鼠，其 HSPC 动员和骨髓外造血明显增加。由于脾脏巨噬细胞和树突状细胞产生 IL-23，骨髓外造血增加与血清中 G-CSF 水平升高有关。这有利于骨髓中的造血谱系向粒细胞而不是巨噬细胞分化，导致成骨细胞支持受损和间充质祖细胞 Cxcl12/SDF-1 产生减少。通过提高 Abca1(-/-)Abcg1(-/-)和 Apoe(-/-)小鼠或 Flt3-ITD 突变介导的骨髓增生性肿瘤小鼠的 HDL 水平，可以逆转更大的 HSPC 动员和骨髓外造血。我们的数据确定了胆固醇外排途径在控制 HSPC 动员中的作用。这可能转化为动脉粥样硬化和血液恶性肿瘤的治疗策略。
