Adiponectin Enhances Quiescence Exit of Murine Hematopoietic Stem Cells and Hematopoietic Recovery Through mTORC1 Potentiation
Adiponectin Enhances Quiescence Exit of Murine Hematopoietic Stem Cells and Hematopoietic Recovery Through mTORC1 Potentiation
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DOI：
10.1002/stem.2640
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发表时间：
2017-07-01
期刊：
影响因子：
5.2
通讯作者：
Kurokawa, Mineo
中科院分区：
文献类型：
--
作者：
Masamoto, Yosuke;Arai, Shunya;Kurokawa, Mineo
化疗药物和电离辐射等骨髓毒性损伤，释放造血干细胞（HSC）补充造血系统的旺盛力量，使休眠的HSC进入细胞周期。考虑到 HSC 内在和外在机制都会强制 HSC 静止，损伤后骨髓 (BM) 环境的剧烈变化（以 BM 脂肪细胞的大量扩张为代表）可能会触发 HSC 激活。然而，据报道，骨髓脂肪细胞是消融骨髓中的主要细胞成分，可抑制造血细胞的增殖，这可能表明骨髓脂肪细胞生成是受损有机体的不合理反应。鉴于脂肪组织是具有多效性功能的内分泌器官，我们假设脂肪细胞衍生因子，尤其是脂联素（一种参与调节粒细胞生成的抗炎脂肪因子）与 HSC 活化有关。清髓干预通过多种机制增加骨髓脂联素，包括脂肪细胞扩张和增加血液扩散。脂联素缺失 (Adipaq-l-) 小鼠在 BM 损伤后表现出造血恢复延迟，Adipoq-1-HSC 更加静止，并且在雷帕霉素复合物 1 (mTORC1) 激活的哺乳动物靶标中存在缺陷。重组脂联素不仅能促进体内 HSC 活化，还能促进细胞因子诱导的体外活化，并以 mTORC1 依赖性方式缩短退出静止的时间。这些数据说明了细胞外在因子脂联素增强 HSC 静止退出以及随后的造血恢复的一个鲜为人知的例子。我们的研究结果还强调脂肪细胞作为脂联素的来源，以确保消融骨髓中造血细胞的增殖爆发。
Myelotoxic injury, such as chemotherapeutic agents and ionizing radiation, unlocks the vigorous power of hematopoietic stem cells (HSCs) to replenish the hematopoietic system, making quiescent HSCs enter the cell cycle. Considering that both HSC-intrinsic and-extrinsic mechanisms enforce quiescence of HSCs, the drastic change in bone marrow (BM) environment after injury, represented by massive expansion of BM adipocytes, might trigger HSC activation. BM adipocytes, the major cellular component in the ablated marrow, however, reportedly suppress proliferation of hematopoietic cells, which may indicate the BM adipocytogenesis is an irrational response of injured organism. Given that adipose tissue is an endocrine organ with pleiotropic functions, we hypothesized that adipocyte-derived factors, especially adiponectin, an antiinflammatory adipokine involved in regulation of granulopoiesis, are implicated in HSC activation. Myeloablative intervention increased BM adiponectin by multiple mechanisms, including adipocyte expansion and increased diffusion from the blood. Adiponectin-null (Adipaq-l-) mice showed delayed hematopoietic recovery after BM injury, with Adipoq-1- HSCs more quiescent and defective in mammalian target of rapamycin complex 1 (mTORC1) activation. Recombinant adiponectin promoted not only HSC activation in vivo but cytokine-induced activation in vitro, and shortened the time for exit from quiescence in an mTORC1-dependent manner. These data illustrate a scarcely-reported example of a cell-extrinsic factor, adiponectin, enhancing quiescence exit of HSCs, and subsequent hematopoietic recovery. Our findings also highlight adipocytes as a source of adiponectin to ensure the proliferative burst of hematopoietic cells in ablated marrow.