Injury-activated transforming growth factor ß controls mobilization of mesenchymal stem cells for tissue remodeling.

ABSTRACT

Upon secretion, transforming growth factor ß (TGFß) is maintained in a sequestered state in extracellular matrix as a latent form. The latent TGFß is considered as a molecular sensor that releases active TGFß 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 TGFß storage in the matrix and its activation is obscure. Here, using several animal models in which latent TGFß is activated in vascular matrix in response to injury of arteries, we show that active TGFß 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. TGFßs were activated in the vascular matrix in both rat and mouse models of mechanical injury of arteries. Importantly, the active TGFß released from the injured vessels is essential to induce the migration of MSCs, and cascade expression of monocyte chemotactic protein-1 stimulated by TGFß amplifies the signal for migration. Moreover, sustained high levels of active TGFß 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 TGFß1 in uninjured mice rapidly mobilized MSCs into circulation. Furthermore, inhibitor of TGFß type I receptor blocked the mobilization and recruitment of MSCs to the injured arteries. Thus, TGFß is an injury-activated messenger essential for the mobilization and recruitment of MSCs to participate in tissue repair/remodeling.