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

Journal Article

Mei Wan ,

Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine

, Baltimore, Maryland,

USA

Mei Wan, Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA,Telephone: 410-502-6598; Fax: 410-502-6414; e-mail: [email protected]

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Changjun Li ,

Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine

, Baltimore, Maryland,

USA

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Gehua Zhen ,

Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine

, Baltimore, Maryland,

USA

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Kai Jiao ,

Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine

, Baltimore, Maryland,

USA

Stomatological College, Fourth Military Medical University

, Xi'an,

People's Republic of China

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Wenying He ,

Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine

, Baltimore, Maryland,

USA

Shihezi Medical Collage, Shihezi Univeristy

, Xinjiang,

People's Republic of China

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Xiaofeng Jia ,

Department of Biomedical EngineeringJohns Hopkins University School of Medicine

, Baltimore, Maryland,

USA

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Weishan Wang ,

Shihezi Medical Collage, Shihezi Univeristy

, Xinjiang,

People's Republic of China

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Chenhui Shi ,

Shihezi Medical Collage, Shihezi Univeristy

, Xinjiang,

People's Republic of China

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Qiujuan Xing ,

Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine

, Baltimore, Maryland,

USA

Longhua Hospital, Shanghai University of Traditional Chinese Medicine

, Shanghai,

People's Republic of China

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Yiu-Fai Chen

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham

, Birmingham, Alabama,

USA

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Published:

22 October 2012

Cite

Mei Wan, Changjun Li, Gehua Zhen, Kai Jiao, Wenying He, Xiaofeng Jia, Weishan Wang, Chenhui Shi, Qiujuan Xing, Yiu-Fai Chen, Suzanne Jan De Beur, Bing Yu, Xu Cao, Injury-Activated Transforming Growth Factor β Controls Mobilization of Mesenchymal Stem Cells for Tissue Remodeling, Stem Cells, Volume 30, Issue 11, November 2012, Pages 2498–2511, https://doi.org/10.1002/stem.1208
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Abstract

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.

Copyright © 2012 AlphaMed Press

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