Exosomes derived from adipose tissues accelerate fibroblasts and keratinocytes proliferation and cutaneous wound healing via miR-92a/Hippo-YAP axis

Delayed wound healing is an urgent clinical issue. Cellular communication involving exosome-borne cargo such as miRNA is a critical mechanism involved in wound healing. This study isolated and identified human adipose tissue-derived exosomes (Exo-ATs). The specific effects of Exo-ATs on keratinocytes and fibroblasts were examined. Enriched miRNAs in Exo-ATs were analyzed, and miR-92a-3p was selected. The transfer of Exo-ATs-derived miR-92a-3p to keratinocytes and fibroblasts was verified. miR-92a-3p binding to LATS2 was examined and the dynamic effects of the miR-92a-3p/LATS2 axis were investigated. In a dorsal skin wound model, the in vivo effects of Exo-ATs on wound healing were examined. Exo-AT incubation increased keratinocytes and fibroblast proliferation, migration, and extracellular matrix (ECM) accumulation. miR-92a-3p, enriched in Exo-ATs, could be transferred to keratinocytes and fibroblasts, resulting in enhanced proliferation, migration, and ECM accumulation. Large tumor suppressor kinase 2 (LATS2) was a direct target of miR-92a-3p. miR-92a-3p inhibitor effects on keratinocytes and fibroblasts could be partially reversed by LATS2 knockdown. In a dorsal skin wound model, Exo-ATs accelerated wound healing through enhanced cell proliferation, collagen deposition, re-epithelialization, and YAP/TAZ activation. In conclusion, Exo-ATs improve skin wound healing by promoting keratinocyte and fibroblast migration and proliferation and collagen production by fibroblast, which could be partially eliminated by miR-92a inhibition through its downstream target LATS2 and the YAP/TAZ signaling. (AU)

Exosomes derived from adipose tissues accelerate fibroblasts and keratinocytes proliferation and cutaneous wound healing via miR-92a/Hippo-YAP axis

Delayed wound healing is an urgent clinical issue. Cellular communication involving exosome-borne cargo such as miRNA is a critical mechanism involved in wound healing. This study isolated and identified human adipose tissue-derived exosomes (Exo-ATs). The specific effects of Exo-ATs on keratinocytes and fibroblasts were examined. Enriched miRNAs in Exo-ATs were analyzed, and miR-92a-3p was selected. The transfer of Exo-ATs-derived miR-92a-3p to keratinocytes and fibroblasts was verified. miR-92a-3p binding to LATS2 was examined and the dynamic effects of the miR-92a-3p/LATS2 axis were investigated. In a dorsal skin wound model, the in vivo effects of Exo-ATs on wound healing were examined. Exo-AT incubation increased keratinocytes and fibroblast proliferation, migration, and extracellular matrix (ECM) accumulation. miR-92a-3p, enriched in Exo-ATs, could be transferred to keratinocytes and fibroblasts, resulting in enhanced proliferation, migration, and ECM accumulation. Large tumor suppressor kinase 2 (LATS2) was a direct target of miR-92a-3p. miR-92a-3p inhibitor effects on keratinocytes and fibroblasts could be partially reversed by LATS2 knockdown. In a dorsal skin wound model, Exo-ATs accelerated wound healing through enhanced cell proliferation, collagen deposition, re-epithelialization, and YAP/TAZ activation. In conclusion, Exo-ATs improve skin wound healing by promoting keratinocyte and fibroblast migration and proliferation and collagen production by fibroblast, which could be partially eliminated by miR-92a inhibition through its downstream target LATS2 and the YAP/TAZ signaling. (AU)

Exosomes derived from adipose tissues accelerate fibroblasts and keratinocytes proliferation and cutaneous wound healing via miR-92a/Hippo-YAP axis.

Delayed wound healing is an urgent clinical issue. Cellular communication involving exosome-borne cargo such as miRNA is a critical mechanism involved in wound healing. This study isolated and identified human adipose tissue-derived exosomes (Exo-ATs). The specific effects of Exo-ATs on keratinocytes and fibroblasts were examined. Enriched miRNAs in Exo-ATs were analyzed, and miR-92a-3p was selected. The transfer of Exo-ATs-derived miR-92a-3p to keratinocytes and fibroblasts was verified. miR-92a-3p binding to LATS2 was examined and the dynamic effects of the miR-92a-3p/LATS2 axis were investigated. In a dorsal skin wound model, the in vivo effects of Exo-ATs on wound healing were examined. Exo-AT incubation increased keratinocytes and fibroblast proliferation, migration, and extracellular matrix (ECM) accumulation. miR-92a-3p, enriched in Exo-ATs, could be transferred to keratinocytes and fibroblasts, resulting in enhanced proliferation, migration, and ECM accumulation. Large tumor suppressor kinase 2 (LATS2) was a direct target of miR-92a-3p. miR-92a-3p inhibitor effects on keratinocytes and fibroblasts could be partially reversed by LATS2 knockdown. In a dorsal skin wound model, Exo-ATs accelerated wound healing through enhanced cell proliferation, collagen deposition, re-epithelialization, and YAP/TAZ activation. In conclusion, Exo-ATs improve skin wound healing by promoting keratinocyte and fibroblast migration and proliferation and collagen production by fibroblast, which could be partially eliminated by miR-92a inhibition through its downstream target LATS2 and the YAP/TAZ signaling.

Exosomes Derived from Human Adipose Mesenchymal Stem Cells Inhibits Fibrosis and Treats Oral Submucous Fibrosis via the miR-181a-5p/Smad2 Axis.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic disease with carcinogenic tendency that poses a non-negligible threat to human health. Exosomes derived from human adipose mesenchymal stem cells (ADSC-Exo) reduces visceral and cutaneous fibroses, but their role in OSF has received little attention. The aim of this study was to investigate the effects of ADSC-Exo on OSF and elucidate the mechanism. METHODS: In brief, ADSCs were extracted from adipose tissues and subjected to flow cytometry and induction culture. Fibroblasts were isolated from human buccal mucosa and subjected to immunofluorescence. Myofibroblasts were obtained from fibroblasts induced by arecoline and identified. Immunofluorescence assay confirmed that myofibroblasts could take up ADSC-Exo. The effects of ADSC-Exo on the proliferative and migratory capacities of myofibroblasts were examined using the Cell Counting Kit-8 and scratch assay. Real-time quantitative polymerase chain reaction (qPCR) was performed to evaluate mothers against decapentaplegic homolog 2 (Smad2), Smad3, Smad7, collagen type 1 (Col1), Col3, alpha smooth muscle actin (α-SMA), fibronectin, and vimentin. Western blotting was performed to detect phospho (p)-Smad2, Smad2, p-Smad2/3, Smad2/3, Smad7, Col1, Col3, α-SMA, fibronectin, and vimentin. Furthermore, the dual-luciferase reporter assay was performed to prove that miR-181a-5p in ADSC-Exo directly inhibited the expression of Smad2 mRNA to regulate the transforming growth factor beta (TGF-ß) pathway. We also performed qPCR and western blotting to verify the results. RESULTS: ADSC-Exo could promote the proliferation and migration of myofibroblasts, reduce the expressions of p-smad2, Smad2, p-smad2/3, Smad2/3, Col1, αSMA, fibronectin, and vimentin and elevated the levels of Smad7 and Col3. In addition, miR-181a-5p was highly expressed in ADSC-Exo and bound to the 3'-untranslated region of Smad2. ADSC-Exo enriched with miR-181a-5p reduced collagen production in myofibroblasts and modulated the TGF-ß pathway. CONCLUSIONS: ADSC-Exo promoted the proliferative and migratory capacities of myofibroblasts and inhibited collagen deposition and trans-differentiation of myofibroblasts in vitro. miR-181a-5p in exosomes targets Smad2 to regulate the TGF-ß pathway in myofibroblasts. ADSC-Exo perform antifibrotic actions through the miR-181a-5p/Smad2 axis and may be a promising clinical treatment for OSF.

The role of long noncoding RNAs as regulators of the epithelial-Mesenchymal transition process in oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC) is a highly invasive and relatively prevalent cancer, accounting for around 3% of all cancers diagnosed. OSCC is associated with bad outcomes, with only 50% overall survival (OS) after five years. The ability of OSCC to invade local and distant tissues relies on the induction of the epithelial-mesenchymal transition (EMT), wherein epithelial cells shed their polarity and cell-to-cell contacts and acquire mesenchymal characteristics. Consequently, a comprehensive understanding of how tumor cell EMT induction is regulated has the potential of direct attempts to prevent tumor progression and metastasis, resulting in better patient outcomes. Several recent studies have established the significance of particular long noncoding RNAs (lncRNAs) in the context of EMT induction. Moreover, lncRNAs regulate a vast array of oncogenic pathways. With a focus on the mechanisms by which the underlined lncRNAs shape the metastatic process and a discussion of their potential utility as clinical biomarkers or targets for therapeutic intervention in patients with OSCC, the present review thus provides an overview of the EMT-related lncRNAs that are dysregulated in OSCC.

Expression profiles of exosomal tRNA-derived fragments and their biological functions in lipomas.

There is evidence that exosomes derived from the lipoma tissue (Exo-LT) have a stronger capacity to promote the proliferation and migration of adipose-derived stem cells (ADSCs) than those from the adipose tissue (Exo-AT). But the Exo-LT do not have a significant effect on the adipogenic differentiation of the ADSCs. Recently, certain exosomal tRNA-derived fragments (tRFs) have been shown to play a crucial role in the pathogenesis of certain tumors. Therefore, it is necessary to identify the differently expressed tRFs in Exo-LT to further elucidate their molecular functions in lipomas. High-throughput sequencing was performed to examine the tRFs and mRNAs from the all samples belonging to the Exo-LT and Exo-AT groups. Target prediction and bioinformatics analysis were performed to explore their downstream mRNAs and biological functions. In total, 456 differently expressed tRFs and tiRNAs were identified in the Exo-LT group, 12 of which were up-regulated and 12 were down-regulated, respectively. Notably, tRF-1001 was most obviously down-regulated and tRF-3004a was most obviously up-regulated in the Exo-LT group. Moreover, among the target genes of tRF-1001 and tRF-3004a, both JAG2 and VSIG4 were significantly down-regulated in the Exo-LT group, while WNT5A, COL1A1, and PPARGC1A were highly expressed in both the Exo-LT and Exo-AT groups. The significant down-regulation of JAG2 and VSIG4 in the Exo-LT group could be due to the fact that Exo-LT had a stronger capacity to promote the proliferation and migration of ADSCs compared to the Exo-AT. The high expression of WNT5A, COL1A1, and PPARGC1A in both the Exo-LT and Exo-AT groups could be due to the similar ability of Exo-LT and Exo-AT to promote the adipogenic differentiation of ADSCs.