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Tissue Engineering and Regenerative Medicine

TISSUE ENGINEERING AND REGENERATIVE MEDICINE

Umbilical Cord-Derived Mesenchymal Stem
a
Departments of Plastic and Cell-Derived Exosomal MicroRNAs Suppress
Reconstruction and
c
Department of Emergency Myofibroblast Differentiation by Inhibiting the
and Trauma, Shanghai
Changhai Hospital Affiliated Transforming Growth Factor-b/SMAD2 Pathway
to Second Military Medical
University, Shanghai, During Wound Healing
People’s Republic of China;
b
Department of Spinal SHUOFANG, a,* CHENXU, b,* YUNTONGZHANG, CHUNYUXUE, CHAOYANG, HONGDABI, XIJINGQIAN, d
a
c
a
a
Surgery,ChangzhengHospital e e,f e,f e,f e,f a
MINJUAN WU, KAIHONG JI, YUNPENG ZHAO, YUE WANG, HOUQI LIU, XIN XING
Affiliated to Second Military
Medical University, Shanghai, Key Words. Myofibroblast x Transforming growth factor-b x Exosome x Mesenchymal stem cells x
People’s Republic of China; MicroRNA
d
Department of
Microbiology, Shanghai Key
Laboratory of Medical ABSTRACT
e
Biodefense, Research Center Excessive scar formation caused by myofibroblast aggregations is of great clinical importance during
of Developmental Biology, skin wound healing. Studies have shown that mesenchymal stem cells (MSCs) can promote skin regen-
f
and Translational Medicine eration, but whether MSCs contribute to scar formation remains undefined. We found that umbilical
Center, Second Military cord-derived MSCs (uMSCs) reduced scar formation and myofibroblast accumulation in a skin-defect
Medical University, Shanghai, mouse model. We found that these functions were mainly dependent on uMSC-derived exosomes
People’s Republic of China (uMSC-Exos)andespeciallyexosomalmicroRNAs.Throughhigh-throughputRNAsequencingandfunc-
tional analysis, we demonstrated that a group of uMSC-Exos enriched in specific microRNAs (miR-21,
*
Contributed equally. -23a, -125b, and -145) played key roles in suppressing myofibroblast formation by inhibiting the trans-
forminggrowthfactor-b2/SMAD2pathway.Finally,usingthestrategyweestablishedtoblockmiRNAs
Correspondence: Xin Xing, M.D.,
Ph.D., Department of Plastic and inside the exosomes, we showed that these specific exosomal miRNAs were essential for the
Reconstruction, Shanghai myofibroblast-suppressing and anti-scarring functions of uMSCs both in vitro and in vivo. Our study
Changhai Hospital Affiliated to revealed a novel role of exosomal miRNAs in uMSC-mediated therapy, suggesting that the clinical ap-
Second Military Medical plication of uMSC-derived exosomes might represent a strategy to prevent scar formation during
University, 168th Chang Hai wound healing. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1425–1439
Road, Shanghai 200433, People’s
Republic of China. Telephone:
86-021-3116-1811; E-Mail:
mone1030@163.com; or Yue SIGNIFICANCE
Wang, Ph.D., Research Center of Exosomes have been identified as a new type of major paracrine factor released by umbilical cord-
Developmental Biology and
Translational Medicine Center, derived mesenchymal stem cells (uMSCs). They have been reported to be an important mediator of
Second Military Medical cell-to-cellcommunication.However,itisstillunclearpreciselywhichmoleculeorgroupofmolecules
University, 800th Xiangyin Road, carried within MSC-derived exosomes can mediate myofibroblast functions, especially in the process
Shanghai 200433, People’s ofwoundrepair.ThepresentstudyexploredthefunctionalrolesofuMSC-exosomalmicroRNAsinthe
Republic of China. Telephone:
86-021-8187-0964; E-Mail: process of myofibroblast formation, which can cause excessive scarring. This is an unreported func-
wangyuesmmu@163.com; or tion of uMSC exosomes. Also, for the first time, the uMSC-exosomal microRNAs were examined by
Houqi Liu, Ph.D., Research Center high-throughput sequencing, with a group of specific microRNAs (miR-21, miR-23a, miR-125b, and
of Developmental Biology and miR-145) found to play key roles in suppressing myofibroblast formation by inhibiting excess
Translational Medicine Center, a-smooth muscle actin and collagen deposition associated with activity of the transforming growth
Second Military Medical
University, 800th Xiangyin Road, factor-b/SMAD2 signaling pathway.
Shanghai 200433, People’s
Republic of China. Telephone:
86-021-8187-0958; E-Mail: result in fibrotic diseases [1, 2]. The transforming
houqiliu@126.com INTRODUCTION
growth factor-b (TGF-b) family has been recog-
Myofibroblasts appear during the contraction
Received November 25, 2015; nizedasapivotalregulatorofcellularproliferation,
accepted for publication April 18, stage of wound healing. For optimal healing of a differentiation, and metabolism in wound healing
2016; published Online First on cutaneous wound, the processes occurring during and tissue repair [3]. Inappropriately high levels of
July 7, 2016. the contraction stage can reduce the surface area TGF-bactivityatwoundsiteshavebeenassociated
©AlphaMed Press and facilitate re-epithelialization. However, aber- with excessive scarring and fibrosis. TGF-b binds
1066-5099/2016/$20.00/0 rations in the wound healing program or other and activates a membrane receptor serine/
http://dx.doi.org/ pathological states can lead to the recruitment threonine kinase complex that phosphorylates
10.5966/sctm.2015-0367 and maintenance of active myofibroblasts and various SMAD family proteins [4]. Phosphorylated

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