Bai L, Shi G, Zhang L, Guan F, Ma Y, Li Q, Cong Y-S, Zhang L
Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing 100021, China.
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
Cell Death Dis. 2014 Mar 27;5(3):e1140. doi: 10.1038/cddis.2014.105.
A tightly controlled balance between hematopoietic stem and progenitor cell compartments is required to maintain normal blood cell homeostasis throughout life, and this balance is regulated by intrinsic and extrinsic cellular factors. Cav-1 is a 22-kDa protein that is located in plasma membrane invaginations and is implicated in regulating neural stem cell and embryonic stem cell proliferation. However, the role of Cav-1 in hematopoietic stem cell (HSC) function is largely unknown. In this study, we used Cav-1(-/-) mice to investigate the role of Cav-1 in HSCs function during aging. The results showed that Cav-1(-/-) mice displayed a decreased percentage of B cells and an increased percentage of M cells in the bone marrow and peripheral blood, and these changes were due to an increased number of HSCs. FACS analysis showed that the numbers of Lin(-)Sca1(+)c-kit(+) cells (LSKs), long-term HSCs (LT-HSCs), short-term HSCs and multipotent progenitors were increased in Cav-1(-/-) mice compared with Cav-1(+/+) mice, and this increase became more pronounced with aging. An in vitro clonogenic assay showed that LT-HSCs from Cav-1(-/-) mice had reduced ability to self-renew. Consistently, an in vivo competitive transplantation assay showed that Cav-1(-/-) mice failed to reconstitute hematopoiesis. Moreover, a Cav-1 deletion disrupted the quiescence of LSKs and promoted cell cycle progression through G2/M phase. In addition, we found that Cav-1 deletion impaired the ability of HSCs to differentiate into mature blood cells. Taken together, these data suggest that Cav-1-deficient cells impaired HSCs quiescence and induced environmental alterations, which limited HSCs self-renewal and function.
在整个生命过程中，造血干细胞和祖细胞区室之间需要严格控制的平衡来维持正常的血细胞稳态，并且这种平衡由内在和外在细胞因子调节。Cav-1是一种22 kDa的蛋白质，位于质膜内陷处，与调节神经干细胞和胚胎干细胞增殖有关。然而，Cav-1在造血干细胞（HSC）功能中的作用在很大程度上尚不清楚。在本研究中，我们使用Cav-1基因敲除小鼠来研究Cav-1在衰老过程中对造血干细胞功能的作用。结果显示，Cav-1基因敲除小鼠骨髓和外周血中B细胞百分比降低，M细胞百分比增加，这些变化是由于造血干细胞数量增加所致。流式细胞术分析表明，与Cav-1野生型小鼠相比，Cav-1基因敲除小鼠中Lin(-)Sca1(+)c-kit(+)细胞（LSKs）、长期造血干细胞（LT-HSCs）、短期造血干细胞和多能祖细胞的数量增加，并且随着衰老这种增加变得更加明显。体外克隆形成试验表明，来自Cav-1基因敲除小鼠的长期造血干细胞自我更新能力降低。一致地，体内竞争性移植试验表明，Cav-1基因敲除小鼠无法重建造血功能。此外，Cav-1缺失破坏了LSKs的静止状态，并促进细胞周期通过G2/M期进展。另外，我们发现Cav-1缺失损害了造血干细胞分化为成熟血细胞的能力。综上所述，这些数据表明，Cav-1缺陷细胞损害了造血干细胞的静止状态并诱导了环境改变，从而限制了造血干细胞的自我更新和功能。
