title: Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway.
abstract: Human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, we isolated and characterized the exosomes from hucMSCs (hucMSC-Ex) and demonstrated that hucMSC-Ex promoted the proliferation, migration, and tube formation of endothelial cells in a dose-dependent manner. Furthermore, we demonstrated that hucMSC-Ex promoted wound healing and angiogenesis in vivo by using a rat skin burn model. We discovered that hucMSC-Ex promoted β-catenin nuclear translocation and induced the increased expression of proliferating cell nuclear antigen, cyclin D3, N-cadherin, and β-catenin and the decreased expression of E-cadherin. The activation of Wnt/β-catenin is critical in the induction of angiogenesis by hucMSC-Ex, which could be reversed by β-catenin inhibitor ICG-001. Wnt4 was delivered by hucMSC-Ex, and the knockdown of Wnt4 in hucMSC-Ex abrogated β-catenin nuclear translocation in endothelial cells. The in vivo proangiogenic effects were also inhibited by interference of Wnt4 expression in hucMSC-Ex. Taken together, these results suggest that hucMSC-Ex-mediated Wnt4 induces β-catenin activation in endothelial cells and exerts proangiogenic effects, which could be an important mechanism for cutaneous wound healing.
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Yaoxiang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Zhaoji
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China icls@ujs.edu.cn lstmmmlst@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China icls@ujs.edu.cn lstmmmlst@163.com.
authors.forename: Wenrong
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D055354:Exosomes / Q000378:metabolism / Q000637:transplantation; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D018919:Neovascularization, Physiologic; D011744:Pyrimidinones / Q000008:administration & dosage; D051381:Rats; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects; D014470:Umbilical Cord / Q000166:cytology; D060528:Wnt4 Protein / Q000096:biosynthesis*; D014945:Wound Healing; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; C555581:WNT4 protein, human; D060528:Wnt4 Protein; D051176:beta Catenin
keywords: Angiogenesis; Exosomes; Regenerative medicine; Wnt4; β-Catenin
references.citation: Cell Biol Int. 2008 Jan;32(1):8-15
references.pmid: 17904875
references.citation: Biochem Biophys Res Commun. 2013 Aug 23;438(2):410-9
references.pmid: 23899518
references.citation: Burns. 2013 Feb;39(1):98-104
references.pmid: 22738824
references.citation: Cell. 2012 Dec 21;151(7):1542-56
references.pmid: 23260141
references.citation: Circ Res. 2007 Mar 30;100(6):782-94
references.pmid: 17395884
references.citation: Am J Physiol Renal Physiol. 2007 May;292(5):F1626-35
references.pmid: 17213465
references.citation: Stem Cell Res. 2010 May;4(3):214-22
references.pmid: 20138817
references.citation: Blood. 2013 May 9;121(19):3997-4006, S1-15
references.pmid: 23532734
references.citation: Tissue Eng Part A. 2013 Jun;19(11-12):1327-35
references.pmid: 23394225
references.citation: J Biol Chem. 2013 Nov 29;288(48):34343-51
references.pmid: 24133215
references.citation: Circ Res. 2004 Mar 19;94(5):678-85
references.pmid: 14739163
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7312-7
references.pmid: 23589885
references.citation: Int J Cancer. 2012 May 1;130(9):2033-43
references.pmid: 21630268
references.citation: Cold Spring Harb Perspect Biol. 2012 Sep;4(9):a007864
references.pmid: 22952392
references.citation: Protein Cell. 2013 Dec;4(12):932-41
references.pmid: 24203759
references.citation: Mediators Inflamm. 2013;2013:127170
references.pmid: 23983401
references.citation: Cancer Lett. 2012 Feb 1;315(1):28-37
references.pmid: 22055459
references.citation: Dis Model Mech. 2013 Mar;6(2):312-22
references.pmid: 23471910
references.citation: Curr Stem Cell Res Ther. 2013 Mar;8(2):144-55
references.pmid: 23279098
references.citation: Exp Cell Res. 2013 May 15;319(9):1317-23
references.pmid: 23291327
references.citation: Vet J. 2014 Nov;202(2):361-6
references.pmid: 25241947
references.citation: Int Orthop. 2013 Dec;37(12):2491-8
references.pmid: 23948983
references.citation: Oncotarget. 2013 Nov;4(11):2057-66
references.pmid: 24185202
references.citation: J Mol Med (Berl). 2014 Apr;92(4):387-97
references.pmid: 24337504
references.citation: Stem Cells Dev. 2013 Mar 15;22(6):845-54
references.pmid: 23002959
references.citation: Biotechnol Lett. 2010 May;32(5):725-32
references.pmid: 20131083
references.citation: Immune Netw. 2013 Aug;13(4):133-40
references.pmid: 24009540
references.citation: Blood. 2014 Dec 11;124(25):3748-57
references.pmid: 25320245
references.citation: Biotechnol Appl Biochem. 2010 Jan;55(1):53-62
references.pmid: 19961436
references.citation: J Neuroimmune Pharmacol. 2013 Dec;8(5):1062-76
references.pmid: 23579931
references.citation: Stem Cells Dev. 2011 Jan;20(1):103-13
references.pmid: 20446811
references.citation: Curr Neurovasc Res. 2013 May;10(2):103-11
references.pmid: 23469950
references.citation: PLoS One. 2010;5(9):e12688
references.pmid: 20856928
references.citation: Cell Cycle. 2007 May 2;6(9):1049-52
references.pmid: 17438375
references.citation: Arthritis Rheum. 2010 Aug;62(8):2467-75
references.pmid: 20506343
references.citation: Curr Opin Nephrol Hypertens. 2010 Jan;19(1):7-12
references.pmid: 19823086
references.citation: Nature. 2005 May 5;435(7038):58-65
references.pmid: 15875013
references.citation: PLoS One. 2012;7(3):e32765
references.pmid: 22427880
references.citation: Int J Biochem Cell Biol. 2012 Nov;44(11):2060-4
references.pmid: 22903023
references.citation: Curr Opin Cell Biol. 2004 Aug;16(4):415-21
references.pmid: 15261674
references.citation: Curr Opin Cell Biol. 2009 Aug;21(4):575-81
references.pmid: 19442504
references.citation: EMBO J. 2014 Jul 1;33(13):1454-73
references.pmid: 24825347
references.citation: Stem Cells. 2015 Jul;33(7):2158-68
references.pmid: 24964196
references.citation: Eur Biophys J. 2008 Mar;37(3):323-32
references.pmid: 18064447
references.citation: Angiogenesis. 2012 Mar;15(1):33-45
references.pmid: 22203239
references.citation: Stem Cells. 2012 Sep;30(9):1985-98
references.pmid: 22736596
references.citation: Blood. 2007 Oct 1;110(7):2440-8
references.pmid: 17536014
references.citation: Liver Int. 2009 Mar;29(3):356-65
references.pmid: 19141029
references.citation: Nat Cell Biol. 2012 Oct;14(10):1036-45
references.pmid: 22983114
references.citation: Curr Opin Genet Dev. 2009 Oct;19(5):476-83
references.pmid: 19864126
references.citation: Stem Cell Res Ther. 2013;4(2):34
references.pmid: 23618405