Abstract
Objective Mesenchymal stem cells (MSCs) are considered a promising therapy for wound healing. Here, we explored the role of c-Jun in diabetic wound healing using human umbilical cord-derived MSCs (hUC-MSCs). Methods Freshly isolated hUC-MSCs were subjected to extensive in vitro subcultivation. The cell proliferative and migratory capacities were assessed by the Cell Counting Kit-8 and scratch assays, respectively. c-Jun expression was evaluated by RT-PCR and western blot analysis. The function of c-Jun was investigated with lentivirus transduction-based gene silencing and overexpression. Diabetes mellitus was induced in SD rats on a high-glucose/fat diet by streptozocin administration. Wounds were created on the dorsal skin. The effects of c-Jun silencing and overexpression on wound closure by hUC-MSCs were examined. Reepithelialization and angiogenesis were assessed by histological and immunohistochemical analysis, respectively. Platelet-derived growth factor A (PDGFA), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) levels were determined by western blot analysis. Results hUC-MSCs showed gradually decreased cell proliferation, migration, and c-Jun expression during subcultivation. c-Jun silencing inhibited cell proliferation and migration, while c-Jun overexpression enhanced proliferation but not migration. Compared with untransduced hUC-MSCs, local subcutaneous injection of c-Jun-overexpressing hUC-MSCs accelerated wound closure, enhanced angiogenesis and reepithelialization at the wound bed, and increased PDGFA and HGF levels in wound tissues. Conclusion c-Jun overexpression promoted hUC-MSC proliferation and migration in vitro and accelerated diabetic wound closure, reepithelization, and angiogenesis by hUC-MSCs in vivo. These beneficial effects of c-Jun overexpression in diabetic wound healing by hUC-MSCs were at least partially mediated by increased PDGFA and HGF levels in wound tissues.
Highlights
Patients with diabetes mellitus (DM) often experience impaired wound healing, which leads to the formation of chronic ulcers
We found that hUC-Mesenchymal stem cells (MSCs) gradually lost their proliferative and migratory capacities as well as c-Jun expression during in vitro expansion, and c-Jun overexpression increased hUC-MSC proliferation and growth factor production
Since vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and hepatocyte growth factor (HGF) are transcriptionally regulated by c-Jun [42,43,44], we examined the levels of these growth factors in wound tissues after cell implantation
Summary
Patients with diabetes mellitus (DM) often experience impaired wound healing, which leads to the formation of chronic ulcers. The underlying pathogenesis is primarily accounted for by a weakened immune system [1], insufficient angiogenesis [2], impaired proliferation and migration of keratinocytes and fibroblasts [3], and diminished production of healing-related growth factors such as vascular endothelial growth factor (VEGF) [4], insulin-like growth factor 1 (IGF1) [5], transforming growth factor-beta (TGF-β) [6], and platelet-derived growth factor (PDGF) [7]. Several recent studies have shown that the administration of MSCs improves diabetic wound healing though epithelialization, angiogenesis, and the formation of granulation tissues [6, 10, 11]. The number of MSCs isolated from tissues is often insufficient to meet the application need [12], and cells are always expanded in vitro following isolation to obtain sufficient
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