Daming Liu1, Fanxuan Kong1, Yong Yuan2, Prem Seth3, Weidong Xu3, Hao Wang1, Fengjun Xiao1, Lisheng Wang1, Qinglin Zhang1, Yuefeng Yang1, Hua Wang4. 1. Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, China; Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China. 2. Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China. 3. Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, Illinois. 4. Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, China; Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address: 18511712135@163.com.
Abstract
PURPOSE: To evaluate the therapeutic effects of decorin (DCN)-modified mesenchymal stem cells (MSCs) on radiation-induced lung injuries (RILIs) and to clarify the underlying mechanisms. METHODS AND MATERIALS: Umbilical cord-derived mesenchymal stem cells (MSCs) were modified with Ad(E1-).DCN to generate DCN-expressing MSCs (DCN-modified MSCs [MSCs.DCN]). In an experimental mouse model of RILI, MSCs.DCN and MSCs.Null [MSCs modified with Ad(E1-).Null] were intravenously engrafted at 6 hours or 28 days after irradiation. The therapeutic effects on lung inflammation and fibrosis were evaluated by histopathologic analysis at 28 days and 3 months after irradiation. Inflammatory cytokines and chemokines were analyzed in both sera and lung tissues, and subtypes of T lymphocytes including regulatory T cells (Tregs) were analyzed in the peripheral blood and spleen. RESULTS: Both MSC treatments could alleviate histopathologic injuries by reducing lymphocyte infiltration, decreasing apoptosis, increasing proliferation of epithelial cells, and inhibiting fibrosis in the later phase. However, treatment with MSCs.DCN resulted in much more impressive therapeutic effects. Moreover, we discovered that MSC treatment reduced the expression of chemokines and inflammatory cytokines and increased the expression of anti-inflammatory cytokines in both the peripheral blood and local pulmonary tissues. An important finding was that MSCs.DCN were much more effective in inducing interferon-γ expression, inhibiting collagen type III α1 expression in pulmonary tissues, and decreasing the proportion of Tregs. Furthermore, our data suggested that treatment during the acute phase (6 hours) after irradiation evoked much stronger responses both in attenuating inflammation and in inhibiting fibrosis than in the later phase (28 days). CONCLUSIONS: MSCs.DCN could attenuate acute inflammation after irradiation and significantly inhibit later fibrosis. Likewise, DCN enhanced the functions of MSCs by targeting profibrotic factors and Tregs.
PURPOSE: To evaluate the therapeutic effects of decorin (DCN)-modified mesenchymal stem cells (MSCs) on radiation-induced lung injuries (RILIs) and to clarify the underlying mechanisms. METHODS AND MATERIALS: Umbilical cord-derived mesenchymal stem cells (MSCs) were modified with Ad(E1-).DCN to generate DCN-expressing MSCs (DCN-modified MSCs [MSCs.DCN]). In an experimental mouse model of RILI, MSCs.DCN and MSCs.Null [MSCs modified with Ad(E1-).Null] were intravenously engrafted at 6 hours or 28 days after irradiation. The therapeutic effects on lung inflammation and fibrosis were evaluated by histopathologic analysis at 28 days and 3 months after irradiation. Inflammatory cytokines and chemokines were analyzed in both sera and lung tissues, and subtypes of T lymphocytes including regulatory T cells (Tregs) were analyzed in the peripheral blood and spleen. RESULTS: Both MSC treatments could alleviate histopathologic injuries by reducing lymphocyte infiltration, decreasing apoptosis, increasing proliferation of epithelial cells, and inhibiting fibrosis in the later phase. However, treatment with MSCs.DCN resulted in much more impressive therapeutic effects. Moreover, we discovered that MSC treatment reduced the expression of chemokines and inflammatory cytokines and increased the expression of anti-inflammatory cytokines in both the peripheral blood and local pulmonary tissues. An important finding was that MSCs.DCN were much more effective in inducing interferon-γ expression, inhibiting collagen type III α1 expression in pulmonary tissues, and decreasing the proportion of Tregs. Furthermore, our data suggested that treatment during the acute phase (6 hours) after irradiation evoked much stronger responses both in attenuating inflammation and in inhibiting fibrosis than in the later phase (28 days). CONCLUSIONS: MSCs.DCN could attenuate acute inflammation after irradiation and significantly inhibit later fibrosis. Likewise, DCN enhanced the functions of MSCs by targeting profibrotic factors and Tregs.