Paracrine action of mesenchymal stromal cells delivered by microspheres contributes to cutaneous wound healing and prevents scar formation in mice.
OBJECTIVE
Accumulating evidence suggests that mesenchymal stromal cells (MSCs) participate in wound healing to favor tissue regeneration and inhibit fibrotic tissue formation. However, the evidence of MSCs to suppress cutaneous scar is extremely rare, and the mechanism remains unidentified. This study aimed to demonstrate whether MSCs-as the result of their paracrine actions on damaged tissues-would accelerate wound healing and prevent cutaneous fibrosis.


METHODS
For efficient delivery of MSCs to skin wounds, microspheres were used to maintain MSC potency. Whether MSCs can accelerate wound healing and alleviate cutaneous fibrosis through paracrine action was investigated with the use of a Transwell co-culture system in vitro and a murine model in vivo.


RESULTS
MSCs cultured on gelatin microspheres fully retained their cell surface marker expression profile, proliferation, differentiation and paracrine potential. Co-cultures of MSCs and fibroblasts indicated that the benefits of MSCs on suppressing fibroblast proliferation and its fibrotic behavior induced by inflammatory cytokines probably were caused by paracrine actions. Importantly, microspheres successfully delivered MSCs into wound margins and significantly accelerated wound healing and concomitantly reduced the fibrotic activities of cells within the wounds and excessive accumulation of extracellular matrix as well as the transforming growth factor-β1/transforming growth factor-β3 ratio.


CONCLUSIONS
This study provides insight into what we believe to be a previously undescribed, multifaceted role of MSC-released protein in reducing cutaneous fibrotic formation. Paracrine action of MSCs delivered by microspheres may thus qualify as a promising strategy to enhance tissue repair and to prevent excessive fibrosis during cutaneous wound healing.
Key Laboratory of Wound Repair and Regeneration of PLA, The First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing, Peoples Republic of China; Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, Peoples Republic of China; Hainan Branch of the Chinese PLA General Hospital, Sanya, Hainan Province, Peoples Republic of China. Electronic address: stellarahuang@sina.com.
Sha
S
Huang
Key Laboratory of Wound Repair and Regeneration of PLA, The First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing, Peoples Republic of China; Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, Peoples Republic of China.
Yan
Y
Wu
Key Laboratory of Wound Repair and Regeneration of PLA, The First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing, Peoples Republic of China; Department of Oncology, Dongtai People's Hospital, Dongtai, Peoples Republic of China.
Dongyun
D
Gao
Key Laboratory of Wound Repair and Regeneration of PLA, The First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing, Peoples Republic of China; Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, Peoples Republic of China. Electronic address: fuxiaobing@vip.sina.com.
Xiaobing
X
Fu
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002921:Cicatrix / Q000517:prevention & control*; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D023421:Models, Animal; D012871:Skin Diseases / Q000473:pathology / Q000517:prevention & control*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000378:metabolism; D014945:Wound Healing
D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3
fibrosis; mesenchymal stromal cells; microspheres; paracrine; wound healing