完好的胆固醇代谢平衡,有助于维持造血干细胞和多向祖细胞(HSPC)处于静息状态。负责跨细胞膜转运胆固醇的三磷酸腺苷结合盒转运因子ABCA1和ABCG1缺陷,可导致小鼠细胞胆固醇流出途径障碍。
这样的小鼠,显示出HSPC动员和髓外造血的急剧增加。髓外造血的急剧增加,是由于脾巨噬细胞和树突状细胞产生的IL-2诱导血清G-CSF水平上升所造成的。
髓外造血的增加,促使骨髓造血谱系的分化决定向粒细胞,而不是向巨噬细胞的分化方向倾斜。这损害了对成骨细胞的支持,并导致间质祖细胞产生Cxcl12/SDF-1因子的减少。
在Abca1-/-Abcg1-/-和ApoE-/ - 小鼠和FLT3-ITD突变介导的骨髓增生性肿瘤小鼠模型中,HSPC的强烈动员和髓外造血可被增高的高密度脂蛋白水平所逆转。FLT3(Fms-like tyrosine kinase, FMS样的酪氨酸激酶3)属于III型受体酪氨酸激酶(receptor tyrosine kinase III, RTK III)家族成员,近年来,许多大样本研究已经证实FLT3的激活突变在AML的发生及疾病的进展中起到十分重要的病理作用。
本研究的数据确定,胆固醇流出途径对HSPC动员具有控制作用。这可能转化为动脉粥样硬化和血液系统恶性肿瘤的治疗策略。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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PMID:
Regulation of Hematopoietic Stem and Progenitor Cell Mobilization by Cholesterol Efflux Pathways
Marit Westerterp, Samuel Gourion-Arsiquaud, Andrew J. Murphy, Alan Shih, Serge Cremers, Ross L. Levine, Alan R. Tall, Laurent Yvan-Charvet
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.