Injury-Activated Transforming Growth Factor β Controls Mobilization of Mesenchymal Stem Cells for Tissue Remodeling

Upon secretion, transforming growth factor beta (TGF beta) is maintained in a sequestered state in extracellular matrix as a latent form. The latent TGF beta is considered as a molecular sensor that releases active TGF beta 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 TGF beta storage in the matrix and its activation is obscure. Here, using several animal models in which latent TGF beta is activated in vascular matrix in response to injury of arteries, we show that active TGF beta 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. TGF beta s were activated in the vascular matrix in both rat and mouse models of mechanical injury of arteries. Importantly, the active TGF beta released from the injured vessels is essential to induce the migration of MSCs, and cascade expression of monocyte chemotactic protein-1 stimulated by TGF beta amplifies the signal for migration. Moreover, sustained high levels of active TGF beta 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 TGF beta 1 in uninjured mice rapidly mobilized MSCs into circulation. Furthermore, inhibitor of TGF beta type I receptor blocked the mobilization and recruitment of MSCs to the injured arteries. Thus, TGF beta is an injury-activated messenger essential for the mobilization and recruitment of MSCs to participate in tissue repair/remodeling. STEM CELLS2012;30:24982511