Injury-activated transforming growth factor β controls mobilization of mesenchymal stem cells for tissue 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.
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. mwan4@jhmi.edu
Mei
M
Wan
Changjun
C
Li
Gehua
G
Zhen
Kai
K
Jiao
Wenying
W
He
Xiaofeng
X
Jia
Weishan
W
Wang
Chenhui
C
Shi
Qiujuan
Q
Xing
Yiu-Fai
YF
Chen
Suzanne
S
Jan De Beur
Bing
B
Yu
Xu
X
Cao
D000818:Animals; D001158:Arteries / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D020212:Carotid Artery Injuries / Q000473:pathology* / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000473:pathology* / Q000503:physiopathology; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood / Q000378:metabolism; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000473:pathology; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000502:physiology*; D053782:Transforming Growth Factor beta3 / Q000097:blood / Q000378:metabolism; D014945:Wound Healing
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3