Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Stem Cells. 2012 Nov;30(11):2498-511. doi: 10.1002/stem.1208.
Upon secretion, transforming growth factor β (TGFβ) is maintained in a sequestered state in extracellular matrix as a latent form. The latent TGFβ is considered as a molecular sensor that releases active TGFβ in response to the perturbations of the extracellular matrix at the situations of mechanical stress, wound repair, tissue injury, and inflammation. The biological implication of the temporal discontinuity of TGFβ storage in the matrix and its activation is obscure. Here, using several animal models in which latent TGFβ is activated in vascular matrix in response to injury of arteries, we show that active TGFβ controls the mobilization and recruitment of mesenchymal stem cells (MSCs) to participate in tissue repair and remodeling. MSCs were mobilized into the peripheral blood in response to vascular injury and recruited to the injured sites where they gave rise to both endothelial cells for re-endothelialization and myofibroblastic cells to form thick neointima. TGFβs were activated in the vascular matrix in both rat and mouse models of mechanical injury of arteries. Importantly, the active TGFβ released from the injured vessels is essential to induce the migration of MSCs, and cascade expression of monocyte chemotactic protein-1 stimulated by TGFβ amplifies the signal for migration. Moreover, sustained high levels of active TGFβ were observed in peripheral blood, and at the same time points following injury, Sca1+ CD29+ CD11b- CD45- MSCs, in which 91% are nestin+ cells, were mobilized to peripheral blood and recruited to the remodeling arteries. Intravenously injection of recombinant active TGFβ1 in uninjured mice rapidly mobilized MSCs into circulation. Furthermore, inhibitor of TGFβ type I receptor blocked the mobilization and recruitment of MSCs to the injured arteries. Thus, TGFβ is an injury-activated messenger essential for the mobilization and recruitment of MSCs to participate in tissue repair/remodeling.
转化生长因子 β（TGFβ）在分泌后以潜伏形式存在于细胞外基质中。潜伏 TGFβ 被认为是一种分子传感器，可在机械应激、伤口修复、组织损伤和炎症等细胞外基质扰动的情况下释放活性 TGFβ。TGFβ 在基质中存储和激活的时间不连续性的生物学意义尚不清楚。在这里，我们使用几种动物模型，其中潜伏 TGFβ 在动脉损伤时在血管基质中被激活，我们表明，活性 TGFβ 控制间充质干细胞（MSCs）的动员和募集，以参与组织修复和重塑。MSCs 响应血管损伤而动员到外周血，并募集到损伤部位，在那里它们产生内皮细胞以进行再内皮化和肌成纤维细胞以形成厚的新生内膜。在动脉机械损伤的大鼠和小鼠模型中，TGFβ 在血管基质中被激活。重要的是，从受损血管释放的活性 TGFβ 对于诱导 MSCs 的迁移是必需的，并且 TGFβ 刺激的单核细胞趋化蛋白-1 的级联表达放大了迁移信号。此外，在损伤后相同的时间点，外周血中观察到持续高水平的活性 TGFβ，同时，Sca1+ CD29+ CD11b- CD45- MSCs（其中 91%为巢蛋白+细胞）被动员到外周血并募集到重塑的动脉中。静脉注射重组活性 TGFβ1 在未受伤的小鼠中迅速将 MSCs 动员到循环中。此外，TGFβ Ⅰ型受体抑制剂阻断了 MSCs 向损伤动脉的动员和募集。因此，TGFβ 是一种损伤激活的信使，对于 MSCs 的动员和募集参与组织修复/重塑是必需的。
