title: HucMSC Exosome-Delivered 14-3-3ζ Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration.
abstract: Numerous studies showed that mesenchymal stem cells derived exosome (MSC-Ex) markedly enhanced tissue regeneration, however, the issue of whether MSC-Ex could control stem cells expansion after a regenerative response to prevent tissue from overcrowding and dysplasia remains to be established. Herein, we found that human umbilical cord MSC (hucMSC)-exosomal14-3-3ζ mediated the binding of YAP and p-LATS by forming a complex to promote the phosphorylation of YAP, which orchestrate exosomal Wnt4 signal in cutaneous regeneration. First, we assessed deep second-degree burn rats treated with hucMSC-Ex and discovered that hucMSC-Ex promoting self-regulation of Wnt/β-catenin signaling at the remodeling phase of cutaneous regeneration. HucMSC-Ex restricted excessive skin cell expansion and collagen deposition at 4 weeks. Under high cell density conditions, hucMSC-Ex inhibited Wnt/β-catenin signaling through induction of YAP phosphorylation. Second, hucMSC-Ex proteomic analysis revealed that 14-3-3 proteins could be transported by exosome. Using gain- and loss-of-function studies, our results showed that hucMSC-exosomal 14-3-3ζ controlled YAP activities and phosphorylation at Ser127 site, and were required for the binding of YAP and p-LATS. Further studies revealed that 14-3-3ζ recruited YAP and p-LATS to form a complex under high cells density status and 14-3-3ζ other than YAP or p-LATS was the key regulatory molecule of this complex. These findings collectively indicate that hucMSC-Ex functions not only as an "accelerator" of the Wnt/β-catenin signal to repair damaged skin tissue but also as a "brake" of the signal by modulating YAP to orchestrate controlled cutaneous regeneration. Stem Cells 2016;34:2485-2500.
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Aihua
authors.initials: A
authors.lastname: Gong
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Zhaoji
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Hailong
authors.initials: H
authors.lastname: Fu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine. lstmmmlst@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine. icls@ujs.edu.cn.|The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, 212000, P. R. China. icls@ujs.edu.cn.
authors.forename: Wenrong
authors.initials: W
authors.lastname: Xu
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002452:Cell Count; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects; D014157:Transcription Factors; D014470:Umbilical Cord / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C572235:YWHAZ protein, human; D051176:beta Catenin; D012694:Serine; D003094:Collagen; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: 14-3-3 protein; Cutaneous regeneration; Exosomes; Stem cells; Wnt; YAP