完好的膽固醇代謝平衡，有助于維持造血干細胞和多向祖細胞（HSPC）處于靜息狀態(tài)。負責跨細胞膜轉(zhuǎn)運膽固醇的三磷酸腺苷結(jié)合盒轉(zhuǎn)運因子ABCA1和ABCG1缺陷,，可導(dǎo)致小鼠細胞膽固醇流出途徑障礙,。
這樣的小鼠,，顯示出HSPC動員和髓外造血的急劇增加,。髓外造血的急劇增加，是由于脾巨噬細胞和樹突狀細胞產(chǎn)生的IL-2誘導(dǎo)血清G-CSF水平上升所造成的,。
髓外造血的增加,，促使骨髓造血譜系的分化決定向粒細胞，而不是向巨噬細胞的分化方向傾斜,。這損害了對成骨細胞的支持,，并導(dǎo)致間質(zhì)祖細胞產(chǎn)生Cxcl12/SDF-1因子的減少。
在Abca1-/-Abcg1-/-和ApoE-/ - 小鼠和FLT3-ITD突變介導(dǎo)的骨髓增生性腫瘤小鼠模型中,，HSPC的強烈動員和髓外造血可被增高的高密度脂蛋白水平所逆轉(zhuǎn),。FLT3（Fms-like tyrosine kinase, FMS樣的酪氨酸激酶3）屬于III型受體酪氨酸激酶（receptor tyrosine kinase III, RTK III）家族成員,，近年來，許多大樣本研究已經(jīng)證實FLT3的激活突變在AML的發(fā)生及疾病的進展中起到十分重要的病理作用,。
本研究的數(shù)據(jù)確定,，膽固醇流出途徑對HSPC動員具有控制作用。這可能轉(zhuǎn)化為動脈粥樣硬化和血液系統(tǒng)惡性腫瘤的治療策略,。(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.
