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Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis.

Sun Z, Wang C, Shi C, Sun F, Xu X, Qian W, Nie S, Han X - Int. J. Mol. Med. (2014)

Bottom Line: Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis.The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1.Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.

ABSTRACT
Acute lung injury may lead to fibrogenesis. However, no treatment is currently available. This study was conducted to determine the effects of bone marrow-derived mesenchymal stem cells (MSCs) in a model of HCl-induced acute lung injury in Sprague-Dawley (SD) rats. Stromal cell-derived factor (SDF)-1 and its receptor CXC chemokine receptor (CXCR)4 have been shown to participate in mobilizing MSCs. Adenovirus carrying the CXCR4 gene was used to transfect MSCs in order to increase the engraftment numbers of MSCs at injured sites. Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis. The results showed that engraftment of MSCs almost differentiated into myofibroblasts, but rarely differentiated into lung epithelial cells. Additionally, it was demonstrated that activated canonical Wnt/β-catenin signaling in injured lung tissue regulated the myofibroblast differentiation of MSCs in vivo. The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1. Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury.

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Mesenchymal stem cell (MSC) transplantation did not ameliorate lung injury and pulmonary fibrosis. (A) Representative photographs of whole lungs from all the experimental groups after 14 and 28 days of HCl-induced lung injury. The appearance of lungs in acute lung injury (ALI) group, ALI+MSC-CXC chemokine receptor (CXCR)4 group and ALI+MSC-GFP group were intumescent and fibrotic. They were large and had several scars. Lungs of control group showed a normal aspect. (B) Representative photomicrographs of lung histopathology in all the experimental groups after 28 days of MSC transplantation. Lung sections were stained with hematoxylin-eosin (H&E). MSC transplantation did not reduce lung injury but may aggravate pulmonary fibrosis. Original magnification, ×100. (C) Masson’s trichrome staining analysis of collagen deposition in each group. The presence of interstitial collagen (blue staining) was increased in ALI group and MSC transplantation groups. Original magnification, ×100.
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f4-ijmm-33-05-1097: Mesenchymal stem cell (MSC) transplantation did not ameliorate lung injury and pulmonary fibrosis. (A) Representative photographs of whole lungs from all the experimental groups after 14 and 28 days of HCl-induced lung injury. The appearance of lungs in acute lung injury (ALI) group, ALI+MSC-CXC chemokine receptor (CXCR)4 group and ALI+MSC-GFP group were intumescent and fibrotic. They were large and had several scars. Lungs of control group showed a normal aspect. (B) Representative photomicrographs of lung histopathology in all the experimental groups after 28 days of MSC transplantation. Lung sections were stained with hematoxylin-eosin (H&E). MSC transplantation did not reduce lung injury but may aggravate pulmonary fibrosis. Original magnification, ×100. (C) Masson’s trichrome staining analysis of collagen deposition in each group. The presence of interstitial collagen (blue staining) was increased in ALI group and MSC transplantation groups. Original magnification, ×100.

Mentions: After lung collection, the macroscopic appearance of ALI lungs was intumescent and fibrotic (Fig. 4A). The lung samples were large, yellowish and had several scars when compared with the saline control lungs. However, ALI+MSC-GFP and ALI+MSC-CXCR4 lungs were similar in appearance to that of the ALI lungs. MSC transplantation did not attenuate lung injury and the fibrotic response.


Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis.

Sun Z, Wang C, Shi C, Sun F, Xu X, Qian W, Nie S, Han X - Int. J. Mol. Med. (2014)

Mesenchymal stem cell (MSC) transplantation did not ameliorate lung injury and pulmonary fibrosis. (A) Representative photographs of whole lungs from all the experimental groups after 14 and 28 days of HCl-induced lung injury. The appearance of lungs in acute lung injury (ALI) group, ALI+MSC-CXC chemokine receptor (CXCR)4 group and ALI+MSC-GFP group were intumescent and fibrotic. They were large and had several scars. Lungs of control group showed a normal aspect. (B) Representative photomicrographs of lung histopathology in all the experimental groups after 28 days of MSC transplantation. Lung sections were stained with hematoxylin-eosin (H&E). MSC transplantation did not reduce lung injury but may aggravate pulmonary fibrosis. Original magnification, ×100. (C) Masson’s trichrome staining analysis of collagen deposition in each group. The presence of interstitial collagen (blue staining) was increased in ALI group and MSC transplantation groups. Original magnification, ×100.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4020487&req=5

f4-ijmm-33-05-1097: Mesenchymal stem cell (MSC) transplantation did not ameliorate lung injury and pulmonary fibrosis. (A) Representative photographs of whole lungs from all the experimental groups after 14 and 28 days of HCl-induced lung injury. The appearance of lungs in acute lung injury (ALI) group, ALI+MSC-CXC chemokine receptor (CXCR)4 group and ALI+MSC-GFP group were intumescent and fibrotic. They were large and had several scars. Lungs of control group showed a normal aspect. (B) Representative photomicrographs of lung histopathology in all the experimental groups after 28 days of MSC transplantation. Lung sections were stained with hematoxylin-eosin (H&E). MSC transplantation did not reduce lung injury but may aggravate pulmonary fibrosis. Original magnification, ×100. (C) Masson’s trichrome staining analysis of collagen deposition in each group. The presence of interstitial collagen (blue staining) was increased in ALI group and MSC transplantation groups. Original magnification, ×100.
Mentions: After lung collection, the macroscopic appearance of ALI lungs was intumescent and fibrotic (Fig. 4A). The lung samples were large, yellowish and had several scars when compared with the saline control lungs. However, ALI+MSC-GFP and ALI+MSC-CXCR4 lungs were similar in appearance to that of the ALI lungs. MSC transplantation did not attenuate lung injury and the fibrotic response.

Bottom Line: Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis.The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1.Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.

ABSTRACT
Acute lung injury may lead to fibrogenesis. However, no treatment is currently available. This study was conducted to determine the effects of bone marrow-derived mesenchymal stem cells (MSCs) in a model of HCl-induced acute lung injury in Sprague-Dawley (SD) rats. Stromal cell-derived factor (SDF)-1 and its receptor CXC chemokine receptor (CXCR)4 have been shown to participate in mobilizing MSCs. Adenovirus carrying the CXCR4 gene was used to transfect MSCs in order to increase the engraftment numbers of MSCs at injured sites. Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis. The results showed that engraftment of MSCs almost differentiated into myofibroblasts, but rarely differentiated into lung epithelial cells. Additionally, it was demonstrated that activated canonical Wnt/β-catenin signaling in injured lung tissue regulated the myofibroblast differentiation of MSCs in vivo. The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1. Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury.

Show MeSH
Related in: MedlinePlus