HucMSC Exosome-Delivered 14-3-3ζ Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration
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- 作者：Bin Zhang ; Yinghong Shi ; Aihua Gong ; Zhaoji Pan ; Hui Shi ; Huan Yang ; Hailong Fu ; Yongmin Yan ; Xu Zhang ; Mei Wang ; Wei Zhu ; Hui Qian and Wenrong Xu
- 刊名：STEM CELLS
- 出版年：2016
- 出版时间：October 2016
- 年：2016
- 卷：34
- 期：10
- 页码：2485-2500
- 全文大小：1679K
- ISSN：1549-4918
文摘
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