Therapeutic potential of umbilical cord mesenchymal stem cells for inhibiting myofibroblastic differentiation of irradiated human lung fibroblasts

Abstract

Radiation-induced lung injury (RILI) limits the benefits of radiotherapy in patients with lung cancer. Radiation-induced differentiation of lung fibroblasts to myofibroblasts plays a key role in RILI. Recent studies have shown that mesenchymal stem cells (MSCs) can protect against lung fibrosis and that Wnt/β catenin signaling is involved in fibrotic processes. In the present study, we explored the therapeutic potential of human umbilical cord MSCs (HUMSCs) for preventing radiation-induced differentiation of human lung fibroblasts (HLFs) to myofibroblasts. There are two advantages in the use of HUMSCs; namely, they are easily obtained and have low immunogenicity. Irradiated HLFs were co-cultured with HUMSCs. Expression of α -smooth muscle actin (α -SMA), a myofibroblast marker, was measured by Western blot analysis and immunohistochemistry. Irradiation (X-rays, 5 Gy) induced the differentiation of HLFs into myofibroblasts, which was inhibited by co-culture with HUMSCs. Irradiation also caused activation of the canonical Wnt/β -catenin signaling in HLFs, as judged by increased phosphorylation of glycogen synthase kinase 3β, nuclear accumulation of β -catenin, and elevated levels of Wnt-inducible signaling protein-1 (WISP-1) in the conditioned medium. However, co-culture with HUMSCs attenuated the radiation-induced activation of the Wnt/β -catenin signaling. We also measured the expression of FRAT1 that can enhance the Wnt/β -catenin signaling by stabilizing β -catenin. Co-culture with HUMSCs decreased FRAT1 protein levels in irradiated nHLFs. Thus, co-culture with HUMSCs attenuated the radiation-induced activation of Wnt/β -catenin signaling in HLFs, thereby inhibiting myofibroblastic differentiation of HLFs. Wnt/β -catenin signaling is a potential therapeutic target for limiting RILI in patients receiving radiotherapy for lung cancer.