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Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Accelerate Cutaneous Wound Healing by Enhancing Angiogenesis through Delivering Angiopoietin-2

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Abstract

The underlying mechanisms of human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes (hucMSC-Exs), which play significant roles in skin wound healing, remain poorly understood. By using a rat model of deep second-degree burn injury, the roles of hucMSC-Exs in angiogenesis and cutaneous wound healing in vivo were investigated. We found that hucMSC-Exs accelerated skin wound healing and angiogenesis, inducing a higher wound-closure rate and increased expression of CD31 in vivo. We also discovered that hucMSC-Exs contained angiopoietin-2 (Ang-2), and treatment with hucMSC-Exs enhanced the expression of the Ang-2 protein in the wound area and human umbilical vein endothelial cells (HUVECs) through exosomal-mediated Ang-2 transfer. Moreover, hucMSC-Exs promoted the proliferative, migratory, and tube-forming ability of HUVECs. Furthermore, overexpression of Ang-2 in hucMSC-Exs further enhanced HUVEC migration and tube formation and exerted therapeutic and proangiogenic effects in cutaneous wounds in rats, whereas knockdown of Ang-2 in hucMSC-Exs abrogated these therapeutic and proangiogenic effects. Taken together, our results indicated that hucMSC-Ex-derived Ang-2 plays a significant role in tube formation of HUVECs and promotion of angiogenesis, and further suggested that hucMSC-Ex-based therapy may serve as a promising therapeutic approach for promoting cutaneous wound healing.

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Abbreviations

hucMSC-Exs:

human umbilical cord mensenchymal stem cell-derived exosomes

RT-qPCR:

quantitative reverse transcription polymerase chain reaction

Ang-1:

angiopoietin-1

Ang-2:

angiopoietin-2

hucMSCs:

human umbilical cord mensenchymal stem cells

HUVECs:

human umbilical vein endothelial cells

MSCs:

mensenchymal stem cells

MSC-Exs:

MSCs derived exosomes

MEM:

minimum essential medium

FBS:

fetal bovine serum

DMEM:

dulbecco’s modified eagle medium

PBS:

phosphatic buffer solution

BCA:

bicinchoninic acid

TEM:

transmission electron microscope

NTA:

nanoparticle tracking analysis

H&E:

hematoxylin and eosin

BSA:

bovine serum albumin

RIPA:

radio immunoprecipitation assay

SDS-PAGE:

sodium dodecylsulphate polyacrylamide gel electrophoresis

HRP:

horseradish peroxidase

DAPI:

4′-6-Diamidino-2-phenylindole

SD:

means ± standard deviation

n.s.:

not significant

TIE2:

tyrosine kinase with Ig and EGF homology domain 2

VEGF:

vascular endothelial growth factor

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Author notes

  1. Jinwen Liu and Zhixin Yan contributed equally to this work.

Authors and Affiliations

  1. Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, School of Medicine, Jiangsu University, 301 Xuefu Road, 212013, Zhenjiang, Jiangsu, People’s Republic of China

    Jinwen Liu, Fuji Yang, Yan Huang, Yao Yu, Liping Zhou, Zixuan Sun & Yongmin Yan

  2. Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, 212000, People’s Republic of China

    Zhixin Yan

  3. Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

    Dawei Cui

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  1. Jinwen Liu
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  3. Fuji Yang
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  4. Yan Huang
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Material preparation, data collection and analysis were performed by Jinwen Liu, Zhixin Yan, Fuji Yang and Yan Huang. Jinwen Liu wrote the first draft of the manuscript and all authors read and approved the final manuscript. Dawei Cui contributed to analysis of data, paper writing and first revision. Yongmin Yan contributed to do experiment design, and also contributed in the manuscript preparation.

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This article belongs to the Topical Collection: Special Issue on Exosomes and Microvesicles: from Stem Cell Biology to Translation in Human Diseases

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Liu, J., Yan, Z., Yang, F. et al. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Accelerate Cutaneous Wound Healing by Enhancing Angiogenesis through Delivering Angiopoietin-2. Stem Cell Rev and Rep 17, 305–317 (2021). https://doi.org/10.1007/s12015-020-09992-7

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