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

Sun,Zhaorui; Wang,Cong; Shi,Chaowen; Sun,Fangfang; Xu,Xiaomeng; Qian,Weiping; Nie,Shinan; Han,Xiaodong

doi:10.3892/ijmm.2014.1672

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

Authors:
- Zhaorui Sun
- Cong Wang
- Chaowen Shi
- Fangfang Sun
- Xiaomeng Xu
- Weiping Qian
- Shinan Nie
- Xiaodong Han
View Affiliations

Affiliations: Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China, State Key Laboratory of Bioelectronics, Southeast University, Nanjing, Jiangsu 210093, P.R. China, Department of Emergency, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
Published online on: February 25, 2014 https://doi.org/10.3892/ijmm.2014.1672
Pages: 1097-1109
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Ware LB and Matthay MA: The acute respiratory distress syndrome. N Engl J Med. 342:1334–1349. 2000. View Article : Google Scholar : PubMed/NCBI
2	Matute-Bello G, Frevert CW and Martin TR: Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 295:L379–L399. 2008. View Article : Google Scholar : PubMed/NCBI
3	Meduri GU: The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment. Eur Respir J. 9:2650–2670. 1996. View Article : Google Scholar : PubMed/NCBI
4	Prockop DJ: Marrow stromal cells as stem cells for continual renewal of nonhematopoietic tissues and as potential vectors for gene therapy. J Cell Biochem Suppl. 30–31:284–285. 1998.PubMed/NCBI
5	Okamoto R, Yajima T, Yamazaki M, et al: Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med. 8:1011–1017. 2002. View Article : Google Scholar : PubMed/NCBI
6	Matsumoto T, Okamoto R, Yajima T, et al: Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine. Gastroenterology. 128:1851–1867. 2005. View Article : Google Scholar : PubMed/NCBI
7	Krause DS: Plasticity of marrow-derived stem cells. Gene Ther. 9:754–758. 2002. View Article : Google Scholar : PubMed/NCBI
8	Asahara T, Murohara T, Sullivan A, et al: Isolation of putative progenitor endothelial cells for angiogenesis. Science. 275:964–967. 1997. View Article : Google Scholar : PubMed/NCBI
9	Lapidot T, Dar A and Kollet O: How do stem cells find their way home? Blood. 106:1901–1910. 2005. View Article : Google Scholar : PubMed/NCBI
10	Son BR, Marquez-Curtis LA, Kucia M, et al: Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells. 24:1254–1264. 2006. View Article : Google Scholar : PubMed/NCBI
11	Liebler JM, Lutzko C, Banfalvi A, et al: Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 295:L285–L292. 2008. View Article : Google Scholar : PubMed/NCBI
12	Lapidot T: Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4 interactions. Ann N Y Acad Sci. 938:83–95. 2001. View Article : Google Scholar : PubMed/NCBI
13	Askari AT, Unzek S, Popovic ZB, et al: Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet. 362:697–703. 2003. View Article : Google Scholar : PubMed/NCBI
14	Ji JF, He BP, Dheen ST and Tay SS: Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells. 22:415–427. 2004. View Article : Google Scholar : PubMed/NCBI
15	Kollet O, Shivtiel S, Chen YQ, et al: HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34⁺stem cell recruitment to the liver. J Clin Invest. 112:160–169. 2003. View Article : Google Scholar : PubMed/NCBI
16	Hashimoto N, Jin H, Liu T, Chensue SW and Phan SH: Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest. 113:243–252. 2004. View Article : Google Scholar : PubMed/NCBI
17	Rojas M, Xu J, Woods CR, et al: Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 33:145–152. 2005. View Article : Google Scholar : PubMed/NCBI
18	Xu J, Mora A, Shim H, Stecenko A, Brigham KL and Rojas M: Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am J Respir Cell Mol Biol. 37:291–299. 2007. View Article : Google Scholar : PubMed/NCBI
19	Cheon SS, Nadesan P, Poon R and Alman BA: Growth factors regulate β-catenin-mediated TCF-dependent transcriptional activation in fibroblasts during the proliferative phase of wound healing. Exp Cell Res. 293:267–274. 2004.
20	Chilosi M, Poletti V, Zamò A, et al: Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol. 162:1495–1502. 2003.
21	Pongracz JE and Stockley RA: Wnt signalling in lung development and diseases. Respir Res. 7:152006. View Article : Google Scholar : PubMed/NCBI
22	Königshoff M, Balsara N, Pfaff EM, et al: Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 3:e21422008.PubMed/NCBI
23	Uematsu K, He B, You L, Xu Z, McCormick F and Jablons DM: Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene. 22:7218–7221. 2003. View Article : Google Scholar : PubMed/NCBI
24	Wang Y, Sun Z, Qiu X, Li Y, Qin J and Han X: Roles of Wnt/β-catenin signaling in epithelial differentiation of mesenchymal stem cells. Biochem Biophys Res Commun. 390:1309–1314. 2009.
25	Sun Z, Wang Y, Gong X, Su H and Han X: Secretion of rat tracheal epithelial cells induces mesenchymal stem cells to differentiate into epithelial cells. Cell Biol Int. 36:169–175. 2012. View Article : Google Scholar : PubMed/NCBI
26	White ES, Atrasz RG, Hu B, et al: Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10). Am J Respir Crit Care Med. 173:112–121. 2006. View Article : Google Scholar : PubMed/NCBI
27	Qiu X, Lin H, Wang Y, et al: Intracavernous transplantation of bone marrow-derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats. J Sex Med. 8:427–436. 2011. View Article : Google Scholar : PubMed/NCBI
28	Cargnoni A, Gibelli L, Tosini A, et al: Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant. 18:405–422. 2009. View Article : Google Scholar : PubMed/NCBI
29	Chang YS, Oh W, Choi SJ, et al: Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats. Cell Transplant. 18:869–886. 2009. View Article : Google Scholar : PubMed/NCBI
30	Galvez BG, Sampaolesi M, Brunelli S, et al: Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability. J Cell Biol. 174:231–243. 2006. View Article : Google Scholar : PubMed/NCBI
31	Romagnani P, Lasagni L, Mazzinghi B, Lazzeri E and Romagnani S: Pharmacological modulation of stem cell function. Curr Med Chem. 14:1129–1139. 2007. View Article : Google Scholar : PubMed/NCBI
32	Ratajczak MZ, Zuba-Surma E, Kucia M, Reca R, Wojakowski W and Ratajczak J: The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia. 20:1915–1924. 2006. View Article : Google Scholar : PubMed/NCBI
33	Song JS, Kang CM, Kang HH, Yoon HK, Kim YK, Kim KH, Moon HS and Park SH: Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis. Exp Mol Med. 42:465–476. 2010. View Article : Google Scholar : PubMed/NCBI
34	Mehrad B, Burdick MD and Strieter RM: Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. Int J Biochem Cell Biol. 41:1708–1718. 2009. View Article : Google Scholar : PubMed/NCBI
35	Phillips RJ, Burdick MD, Hong K, et al: Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest. 114:438–446. 2004. View Article : Google Scholar : PubMed/NCBI
36	Antoniou KM, Papadaki HA, Soufla G, et al: Investigation of bone marrow mesenchymal stem cells (BM MSCs) involvement in Idiopathic Pulmonary Fibrosis (IPF). Respir Med. 104:1535–1542. 2010. View Article : Google Scholar : PubMed/NCBI
37	Ortiz LA, Gambelli F, McBride C, et al: Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA. 100:8407–8411. 2003. View Article : Google Scholar : PubMed/NCBI
38	Fine A: Marrow cells as progenitors of lung tissue. Blood Cells Mol Dis. 32:95–96. 2004. View Article : Google Scholar : PubMed/NCBI
39	Kotton DN, Summer R and Fine A: Lung stem cells: new paradigms. Exp Hematol. 32:340–343. 2004. View Article : Google Scholar : PubMed/NCBI
40	Ling L, Nurcombe V and Cool SM: Wnt signaling controls the fate of mesenchymal stem cells. Gene. 433:1–7. 2009. View Article : Google Scholar : PubMed/NCBI
41	Pinto D and Clevers H: Wnt control of stem cells and differentiation in the intestinal epithelium. Exp Cell Res. 306:357–363. 2005. View Article : Google Scholar : PubMed/NCBI
42	Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI
43	Van Amerongen R and Berns A: Knockout mouse models to study Wnt signal transduction. Trends Genet. 22:678–689. 2006.PubMed/NCBI
44	Scotton CJ and Chambers RC: Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest. 132:1311–1321. 2007. View Article : Google Scholar : PubMed/NCBI