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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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Detection of mesenchymal stem cell (MSC) differentiation 14 days after transplantation in injured lung. Engraftment of MSCs in lung shown as GFP+ (green fluorescent cells, white arrows) and antibodies to specific cell-type markers (red); co-localization in each case appears yellow. (A–C) Normal control group for α-SMA, CK18 and IgG. (D–R) Immunofluorescent staining for the engraftment of MSC differentiation in the ALI+MSC-CXC chemokine receptor (CXCR)4 group demonstrated that MSCs expressed myofibroblast or fibroblast markers, but did not express epithelial markers. Engraftment of MSCs was almost differentiated into myofibroblasts or fibroblasts, however, rarely differentiated into lung epithelial cells. Nuclear staining was performed using 4′,6-diamidino-2-phenylindole (DAPI). Scale bar, 50 μm.
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f6-ijmm-33-05-1097: Detection of mesenchymal stem cell (MSC) differentiation 14 days after transplantation in injured lung. Engraftment of MSCs in lung shown as GFP+ (green fluorescent cells, white arrows) and antibodies to specific cell-type markers (red); co-localization in each case appears yellow. (A–C) Normal control group for α-SMA, CK18 and IgG. (D–R) Immunofluorescent staining for the engraftment of MSC differentiation in the ALI+MSC-CXC chemokine receptor (CXCR)4 group demonstrated that MSCs expressed myofibroblast or fibroblast markers, but did not express epithelial markers. Engraftment of MSCs was almost differentiated into myofibroblasts or fibroblasts, however, rarely differentiated into lung epithelial cells. Nuclear staining was performed using 4′,6-diamidino-2-phenylindole (DAPI). Scale bar, 50 μm.

Mentions: Although MSC transplantation decreased inflammatory cytokine production, the beneficial effects of MSCs on lung injury were not observed. We hypothesized that MSC differentiation is important in lung repair or remodeling thereof. To investigate the differentiation of engraftment MSCs in vivo, we used immunofluorescent staining to detect the epithelial and fibroblast marker expression of MSCs 14 days after MSCs transplantation in ALI+MSC-CXCR4 group. We found that engraftment of MSCs (GFP+ cells show in green) expressed myofibroblast marker α-smooth muscle actin (α-SMA) and fibroblast marker vimentin (Fig. 6A), but rarely expressed epithelial markers CK18, CK19 and SP-C (Fig. 6B). These data suggested that MSCs almost differentiated into lung fibroblasts or myofibroblasts, but did not differentiate into lung epithelial cells. These fibroblasts differentiated from exogenous MSCs may contribute to pulmonary fibrogenesis. Some molecules or signaling pathway may be involved in the regulation of MSCs differentiation at the injury sites.


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)

Detection of mesenchymal stem cell (MSC) differentiation 14 days after transplantation in injured lung. Engraftment of MSCs in lung shown as GFP+ (green fluorescent cells, white arrows) and antibodies to specific cell-type markers (red); co-localization in each case appears yellow. (A–C) Normal control group for α-SMA, CK18 and IgG. (D–R) Immunofluorescent staining for the engraftment of MSC differentiation in the ALI+MSC-CXC chemokine receptor (CXCR)4 group demonstrated that MSCs expressed myofibroblast or fibroblast markers, but did not express epithelial markers. Engraftment of MSCs was almost differentiated into myofibroblasts or fibroblasts, however, rarely differentiated into lung epithelial cells. Nuclear staining was performed using 4′,6-diamidino-2-phenylindole (DAPI). Scale bar, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6-ijmm-33-05-1097: Detection of mesenchymal stem cell (MSC) differentiation 14 days after transplantation in injured lung. Engraftment of MSCs in lung shown as GFP+ (green fluorescent cells, white arrows) and antibodies to specific cell-type markers (red); co-localization in each case appears yellow. (A–C) Normal control group for α-SMA, CK18 and IgG. (D–R) Immunofluorescent staining for the engraftment of MSC differentiation in the ALI+MSC-CXC chemokine receptor (CXCR)4 group demonstrated that MSCs expressed myofibroblast or fibroblast markers, but did not express epithelial markers. Engraftment of MSCs was almost differentiated into myofibroblasts or fibroblasts, however, rarely differentiated into lung epithelial cells. Nuclear staining was performed using 4′,6-diamidino-2-phenylindole (DAPI). Scale bar, 50 μm.
Mentions: Although MSC transplantation decreased inflammatory cytokine production, the beneficial effects of MSCs on lung injury were not observed. We hypothesized that MSC differentiation is important in lung repair or remodeling thereof. To investigate the differentiation of engraftment MSCs in vivo, we used immunofluorescent staining to detect the epithelial and fibroblast marker expression of MSCs 14 days after MSCs transplantation in ALI+MSC-CXCR4 group. We found that engraftment of MSCs (GFP+ cells show in green) expressed myofibroblast marker α-smooth muscle actin (α-SMA) and fibroblast marker vimentin (Fig. 6A), but rarely expressed epithelial markers CK18, CK19 and SP-C (Fig. 6B). These data suggested that MSCs almost differentiated into lung fibroblasts or myofibroblasts, but did not differentiate into lung epithelial cells. These fibroblasts differentiated from exogenous MSCs may contribute to pulmonary fibrogenesis. Some molecules or signaling pathway may be involved in the regulation of MSCs differentiation at the injury sites.

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