Placental mesenchymal stem cells-secreted proenkephalin suppresses the p38 MAPK signaling to block hyperproliferation of keloid fibroblasts.

BACKGROUND

Thanks to their multi-potency and secretory functions, mesenchymal stem cells (MSCs) have long been established as an ideal cell type for skin wound healing and a candidate therapeutic strategy for excessive pathological scarring in the meantime. This study focuses on the effect of placental MSCs (PMSCs) on the activity of keloid fibroblasts (KFs) and the potential involvement of proenkephalin (PENK).

METHODS

Secretory protein of PMSC that are lowly expressed in KFs were predicted by bioinformatics analyses. The expression of PENK in KFs was detected by RT-qPCR and western blot analysis. PMSCs were co-cultured with KFs and dermal fibroblasts (DFs) to examine their effect on proliferation, migration, invasion, and apoptosis of the distinct cell types. PENK secretion by PMSCs and its uptake by KFs were examined by ELISA, WB, and immunofluorescence staining. Loss-of-functions of PENK and p38-MAPK were induced to examine the activity of KFs in vitro and in mice.

RESULTS

PENK, a secretory protein of PMSCs, was conspicuously downregulated in KFs compared to normal DFs. PMSC stimulation suppressed proliferation, migration, invasion, and resistance to apoptosis of the co-cultured KFs but not DFs, which was ascribed to the upregulation of PENK protein in KFs. PMSCs-secreted PENK suppressed p38 phosphorylation in KFs. The proliferative and aggressive properties of KFs in vitro and the nodule-forming capacity of KFs in vivo were promoted upon PENK downregulation but suppressed by the p38 MAPK inhibitor SB202190.

CONCLUSION

This work unravels that PMSCs-secreted PENK suppresses the p38 MAPK signaling to block hyperproliferation of KFs.