Tohoku J. Exp. Med., 2015 July, 236(3)

Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells for Inhibiting Myofibroblastic Differentiation of Irradiated Human Lung Fibroblasts

CHUNYANG ZHANG,^1,2 YAN ZHU,¹ YAN ZHANG,¹ LIANRU GAO,³ NINGKUN ZHANG³ and HUASONG FENG¹

¹Respiratory Department, Navy General Hospital, Beijing, P.R. China
²China Medical School of Chinese PLA, Beijing, P.R. China
³Center of Cardiology, Navy General Hospital, Beijing, P.R. China

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.

keywords —— Keywords: lung fibroblasts; radiation-induced lung injury; transwell co-culture; umbilical cord mesenchymal stem cells; Wnt/β-catenin signaling

© 2015 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2015, 236, 209-217

Correspondence: Huasong Feng, Respiratory Department, Navy General Hospital, No.6 Fucheng Road, Haidian District, Beijing 100048, P.R. China.

e-mail: fenghsmedsci@126.com