Brief Report: The Differential Roles of mTORC1 and mTORC2 in Mesenchymal Stem Cell Differentiation
Brief Report: The Differential Roles of mTORC1 and mTORC2 in Mesenchymal Stem Cell Differentiation
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DOI：
10.1002/stem.1931
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发表时间：
2015-04-01
期刊：
影响因子：
5.2
通讯作者：
Zannettino, Andrew C. W.
中科院分区：
文献类型：
--
作者：
Martin, Sally K.;Fitter, Stephen;Zannettino, Andrew C. W.
脂肪细胞（AdCs）和成骨细胞（OB）均来源于间充质干细胞（MSC），并且向任一谱系的分化既相互排斥又受转录控制。最近的研究表明，哺乳动物雷帕霉素靶蛋白（mTOR）通路在决定MSC命运中起重要作用，抑制mTOR可促进OB分化并抑制AdC分化。mTOR在两种不同的多蛋白复合物mTORC 1和mTORC 2中发挥作用，每种复合物分别含有独特的衔接蛋白raptor或rictor。虽然用于研究mTOR信号传导的化合物，如雷帕霉素和相关类似物，主要抑制mTORC 1，但长期暴露也会破坏mTORC 2功能，混淆抑制剂研究的解释。因此，mTORC 1和mTORC 2对MSC命运决定的相对贡献仍不清楚。在这项研究中，我们使用Cre/loxP系统产生Rptor（RapKO）或Rictor（RicKO）缺陷的原代小鼠MSC。Cre介导的Rptor或Rictor缺失分别导致mTORC 1和mTORC 2信号传导受损。在谱系诱导培养条件下，RapKO MSC显示出形成载脂AdCs的能力降低和形成矿化基质的能力增加。相反，RicKO MSC显示成骨分化能力降低和成脂分化潜能增强。总之，我们的研究结果揭示了mTORC 1和mTORC 2在MSC谱系定型中的不同作用。干细胞2015;33：1359-1365
Adipocytes (AdCs) and osteoblasts (OBs) are derived from mesenchymal stem cells (MSCs) and differentiation toward either lineage is both mutually exclusive and transcriptionally controlled. Recent studies implicate the mammalian target of rapamycin (mTOR) pathway as important in determining MSC fate, with inhibition of mTOR promoting OB differentiation and suppressing AdC differentiation. mTOR functions within two distinct multiprotein complexes, mTORC1 and mTORC2, each of which contains the unique adaptor protein, raptor or rictor, respectively. While compounds used to study mTOR signaling, such as rapamycin and related analogs, primarily inhibit mTORC1, prolonged exposure can also disrupt mTORC2 function, confounding interpretation of inhibitor studies. As a result, the relative contribution of mTORC1 and mTORC2 to MSC fate determination remains unclear. In this study, we generated primary mouse MSCs deficient in either Rptor (RapKO) or Rictor (RicKO) using the Cre/loxP system. Cre-mediated deletion of Rptor or Rictor resulted in impaired mTORC1 and mTORC2 signaling, respectively. Under lineage-inductive culture conditions, RapKO MSCs displayed a reduced capacity to form lipid-laden AdCs and an increased capacity to form a mineralized matrix. In contrast, RicKO MSCs displayed reduced osteogenic differentiation capacity and enhanced adipogenic differentiation potential. Taken together, our findings reveal distinct roles for mTORC1 and mTORC2 in MSC lineage commitment. Stem Cells2015;33:1359-1365