Department of Dermtology, Jilin Central Hospital, Jilin 132001, Jilin, PR China; Department of Dermtology, Affiliated Hospital of Yanbian University, Yanji 133000, Jilin, PR China.
Department of Dermtology, Jilin Central Hospital, Jilin 132001, Jilin, PR China.
Tissue Cell. 2023 Dec;85:102218. doi: 10.1016/j.tice.2023.102218. Epub 2023 Sep 11.
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).
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.
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.
This work unravels that PMSCs-secreted PENK suppresses the p38 MAPK signaling to block hyperproliferation of KFs.
间充质干细胞（MSCs）因其多能性和分泌功能，长期以来一直被认为是皮肤伤口愈合的理想细胞类型，同时也是病理性瘢痕过度形成的候选治疗策略。本研究关注胎盘间充质干细胞（PMSCs）对瘢痕疙瘩成纤维细胞（KFs）活性的影响及其与前脑啡肽（PENK）的潜在关系。
通过生物信息学分析预测 PMSC 中低表达的 KF 分泌蛋白。通过 RT-qPCR 和 Western blot 分析检测 PENK 在 KF 中的表达。将 PMSC 与 KF 和真皮成纤维细胞（DF）共培养，以观察其对不同细胞类型增殖、迁移、侵袭和凋亡的影响。通过 ELISA、WB 和免疫荧光染色检测 PMSC 分泌的 PENK 及其被 KF 摄取。通过诱导 PENK 和 p38-MAPK 的功能丧失，在体外和小鼠体内检测 KF 的活性。
与正常 DF 相比，PENK 是 PMSC 的一种分泌蛋白，在 KF 中明显下调。PMSC 刺激抑制了共培养的 KF 而非 DF 的增殖、迁移、侵袭和抗凋亡能力，这归因于 KF 中 PENK 蛋白的上调。PMSC 分泌的 PENK 抑制了 KF 中的 p38 磷酸化。PENK 下调促进了 KF 在体外的增殖和侵袭能力以及体内的结节形成能力，而 p38 MAPK 抑制剂 SB202190 则抑制了这一过程。
本研究揭示了 PMSCs 分泌的 PENK 通过抑制 p38 MAPK 信号通路来抑制 KF 的过度增殖。
