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HucMSC Exosome‐Delivered 14‐3‐3ζ Orchestrates Self‐Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration

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