Bone Marrow-Derived Mesenchymal Stem Cells Expressing Thioredoxin 1 Attenuate Bleomycin-Induced Skin Fibrosis and Oxidative Stress in Scleroderma

Abstract

Systemic sclerosis (SSc) is an autoimmune disorder that affects multiple organs. It is characterized by a thickening of the dermis and connective tissue caused by collagen accumulation, and vascular injuries that induce hypoxia. The present study investigated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BMSCs) expressing thioredoxin 1 (Trx-1) in treating SSc-mediated skin disease after transplantation into a bleomycin-induced murine model. Mice with bleomycin-induced SSc were subcutaneously injected with BMSCs or Trx-1-overexpressing BMSCs and exposed to hypoxic conditions for 48 hours. Two weeks later, skin tissue samples were collected to assess fibrosis, oxidative stress, and angiogenesis by western blotting, ELISA, and histologic and immunofluorescence approaches. In vivo experiments showed that Trx-1-overexpressing BMSCs inhibited hypoxia-induced apoptosis and inhibited fibrosis under hypoxic conditions, possibly by downregulating transforming growth factor-β. Trx-1-overexpressing BMSCs also promoted the formation of tubular-like structures by endothelial progenitor cells, indicating that Trx-1 can promote angiogenesis in bleomycin-induced SSc. These results demonstrate that the transplantation of Trx-1-overexpressing BMSCs restored normal skin tissue in a mouse model of bleomycin-induced SSc, highlighting the therapeutic potential of engineered BMSCs for treating SSc.

Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress

“…Increased ROS production in the skin causes oxidative stress, which can lead to apoptosis. It has been reported that oxidative stress-induced apoptotic cells were increased in the bleomycininduced fibrotic skin, and transplantation of mesenchymal stem cells overexpressing Trx-1 significantly inhibited oxidative stress and dermal fibrosis induced by bleomycin [44]. In addition, SSc fibroblasts were extremely sensitive to oxidative stress-induced apoptosis [39].…”

Progress in the mechanism and targeted drug therapy for COPD

“…286 Trx inhibits bleomycininduced skin fibrosis by down-regulating TGF-β. 287 Trx overexpression inhibits airway remodelling by inhibiting TGF-β1 and EGFR. 288 Regulating cAMP cAMP plays a protective role in COPD inflammation through its effector proteins EPAC and PKA.…”

Mesenchymal Stem Cells in Systemic Sclerosis: Allogenic or Autologous Approaches for Therapeutic Use?

“…Similarly, human UC-MSCs over-expressing angiotensin-converting enzyme 2 (ACE2) were more efficient than naïve UC-MSCs to decrease collagen content, fibrotic, and pro-inflammatory factors while increasing anti-oxidative and anti-inflammatory mediators (56). Thioredoxin 1 (Trx-1)-overexpressing BM-MSCs were also shown to inhibit apoptosis and fibrosis under hypoxic conditions and to promote the formation of tubular-like structures by endothelial cells in bleomycin-induced lung injury (57). Indeed, strategies for enhancing MSCs survival and/or efficiency have been demonstrated to be of interest in preclinical models of SSc.…”