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Tissue-Specific Stem Cells
Article first published online: 22 OCT 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 11, pages 2498–2511, November 2012
How to Cite
Wan, M., Li, C., Zhen, G., Jiao, K., He, W., Jia, X., Wang, W., Shi, C., Xing, Q., Chen, Y.-F., Jan De Beur, S., Yu, B. and Cao, X. (2012), Injury-Activated Transforming Growth Factor β Controls Mobilization of Mesenchymal Stem Cells for Tissue Remodeling. STEM CELLS, 30: 2498–2511. doi: 10.1002/stem.1208
Author contributions: M.W.: conception and design, financial support, collection and assembly of data, data analysis and interpretation, and manuscript writing, C.L., G.Z., K.J., W.H., X.J., W.W., C.S., Q.X., and B.Y.: provision of study material, collection and assembly of data, Y.-F.C. and S.J.D.B.: data analysis and interpretation; X.C.: conception and design, financial support, data analysis and Interpretation, and manuscript writing.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS August 21, 2012.
- Issue published online: 22 OCT 2012
- Article first published online: 22 OCT 2012
- Accepted manuscript online: 21 AUG 2012 08:21AM EST
- Manuscript Accepted: 25 JUL 2012
- Manuscript Received: 26 MAR 2012
- National Institutes of Health. Grant Numbers: DK083350, AR053973
- TGFβ activation;
- Mesenchymal stem cells;
- Cell mobilization;
- Vascular remodeling
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. STEM CELLS2012;30:2498–2511