YAP and Wnt3a independently promote AECIIs proliferation and differentiation by increasing nuclear β‑catenin expression in experimental bronchopulmonary dysplasia

Jia,Xianxian; Wu,Bo; Huang,Jinhui; Fan,Lin; Yang,Miao; Xu,Wei

doi:10.3892/ijmm.2020.4791

YAP and Wnt3a independently promote AECIIs proliferation and differentiation by increasing nuclear β‑catenin expression in experimental bronchopulmonary dysplasia

Authors:
- Xianxian Jia
- Bo Wu
- Jinhui Huang
- Lin Fan
- Miao Yang
- Wei Xu
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Affiliations: Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: November 18, 2020 https://doi.org/10.3892/ijmm.2020.4791
Pages: 195-206
Copyright: © Jia et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Arrested alveolar development is the main pathological characteristic of neonatal bronchopulmonary dysplasia (BPD); however, a number of studies aiming to improve alveolarization have focused on alveolar epithelial cell damage and impairment. Previously, the authors reported that the Wnt signaling plays a key role in alveolar injury and repair by regulating alveolar epithelial type II cell (AECII) proliferation and differentiation. In the present study, the authors wished to investigate whether Yes‑associated protein (YAP), a transcriptional coactivator in the Hippo signaling pathway, affects AECII proliferation and differentiation via the Wnt/β‑catenin pathway in BPD. It was found that YAP regulated AECII proliferation and differentiation. A decreased expression of YAP, Wnt3a and nuclear β‑catenin was observed in lung tissues affected by BPD. In vitro, YAP and Wnt3a overexpression in BPD promoted AECII proliferation and differentiation into AECIs by increasing the nuclear transfer of β‑catenin and vice versa. The effects of a decreased Wnt3a expression in primary AECIIs in BPD were compensated by YAP overexpression, as were the effects of Wnt3a knockdown in primary AECIIs. On the whole, the findings of the present study demonstrate that YAP and Wnt3a independently promote AECII proliferation and differentiation in experimental BPD by increasing the nuclear β‑catenin levels. Therefore, Wnt3a or YAP may be candidate regulatory targets for improving the outcomes of BPD.

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1	Li W, Chen Y, Zhang J, Hong L, Yuan N, Wang X and Lv H: IKBKE upregulation is positively associated with squamous cell carcinoma of the lung in vivo and malignant transformation of human bronchial epithelial cells in vitro. Med Sci Monit. 21:1577–1586. 2015. View Article : Google Scholar : PubMed/NCBI
2	O'Reilly M and Thébaud B: Animal models of bronchopulmonary dysplasia. The term rat models Am J Physiol Lung Cell Mol Physiol. 307:L948–L958. 2014. View Article : Google Scholar
3	Islam JY, Keller RL, Aschner JL, Hartert TV and Moore PE: Understanding the short- and long-term respiratory outcomes of prematurity and bronchopulmonary dysplasia. Am J Respir Crit Care Med. 192:134–156. 2015. View Article : Google Scholar : PubMed/NCBI
4	Lodha A, Seshia M, McMillan DD, Barrington K and Yang J: Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr. 169:33–38. 2015. View Article : Google Scholar
5	Williams MC: Alveolar type I cells: Molecular phenotype and development. Annu Rev Physiol. 65:669–695. 2003. View Article : Google Scholar
6	Miyake Y, Kaise H, Isono KI, Koseki H, Kohno K and Tanaka M: Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II Cells. J Immunol. 178:5001–5009. 2007. View Article : Google Scholar : PubMed/NCBI
7	Mason RJ: Biology of alveolar type II cells. Respirology. 11:S12–S15. 2006. View Article : Google Scholar : PubMed/NCBI
8	Shafa M, Ionescu LI, Vadivel A, Collins JJ, Xu L, Zhong S, Kang M, de Caen G, Daneshmand M, Shi J, et al: Human induced pluripotent stem cell-derived lung progenitor and alveolar epithelial cells attenuate hyperoxia-induced lung injury. Cytotherapy. 20:108–125. 2018. View Article : Google Scholar
9	Vega MA, Chupin C, Pascariu M, Privé A, Dagenais A, Berthiaume Y and Brochiero E: Dexamethasone fails to improve bleomycin-induced acute lung injury in mice. Physiol Rep. 7:e142532019.
10	Quantius J, Schmoldt C, Vazquez-Armendariz AI, Becker C, El Agha E, Wilhelm J, Morty RE, Vadász I, Mayer K, Gattenloehner S, et al: Influenza virus infects epithelial stem/progenitor cells of the distal lung: Impact on Fgfr2b-driven epithelial repair. PLoS Pathog. 12:e10055442016. View Article : Google Scholar : PubMed/NCBI
11	Yagi R, Chen LF, Shigesada K, Murakami Y and Ito Y: A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18:2551–2562. 1999. View Article : Google Scholar : PubMed/NCBI
12	Meng Z, Moroishi T and Guan KL: Mechanisms of hippo pathway regulation. Genes Dev. 30:1–17. 2016. View Article : Google Scholar : PubMed/NCBI
13	Pan H, Xie Y, Zhang Z, Li K, Hu D, Zheng X, Fan Q and Tang T: YAP-Mediated mechanotransduction regulates osteogenic and adipogenic differentiation of BMSCs on hierarchical structure. Mechanisms of hippo pathway regulation. Colloids Surf B Biointerfaces. 152:344–353. 2017. View Article : Google Scholar : PubMed/NCBI
14	Barry ER, Morikawa T, Butler BL, Shrestha K, de la Rosa R, Yan KS, Fuchs CS, Magness ST, Smits R, Ogino S, et al: Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature. 493:106–110. 2013. View Article : Google Scholar :
15	Sun C, De Mello V, Mohamed A, Quiroga HP, Garcia-Munoz A, Al Bloshi A, Tremblay AM, von Kriegsheim A, Collie-Duguid E and Vargesson N: Common and distinctive functions of the hippo effectors taz and yap in skeletal muscle stem cell function. Stem Cells. 35:1958–1972. 2017. View Article : Google Scholar : PubMed/NCBI
16	Liu Z, Wu H, Jiang K, Wang Y, Zhang W, Chu Q, Li J, Huang H, Cai T, Ji H, et al: MAPK-Mediated YAP activation controls mechanical-tension-induced pulmonary alveolar regeneration. Cell Rep. 16:1810–1819. 2016. View Article : Google Scholar : PubMed/NCBI
17	Lange AW, Sridharan A, Xu Y, Stripp BR, Perl AK and Whitsett JA: Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung. J Mol Cell Biol. 7:35–47. 2015. View Article : Google Scholar :
18	Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, et al: Inactivation of YAP oncoprotein by the hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21:2747–2761. 2007. View Article : Google Scholar : PubMed/NCBI
19	LaCanna R, Liccardo D, Zhang P, Tragesser L, Wang Y, Cao T, Chapman HA, Morrisey EE, Shen H, Koch WJ, et al: Yap/Taz regulate alveolar regeneration and resolution of lung inflammation. J Clin Invest. 129:2107–2122. 2019. View Article : Google Scholar : PubMed/NCBI
20	Sun T, Huang Z, Zhang H, Posner C, Jia G, Ramalingam TR, Xu M, Brightbill H, Egen JG, Dey A and Arron JR: TAZ is required for lung alveolar epithelial cell differentiation after injury. JCI Insight. 5:e1286742019. View Article : Google Scholar
21	Seo E, Basu-Roy U, Gunaratne PH, Coarfa C, Lim DS, Basilico C and Mansukhani A: SOX2 regulates YAP1 to maintain stemness and determine cell fate in the osteoadipo lineage. Cell Rep. 3:2075–2087. 2013. View Article : Google Scholar : PubMed/NCBI
22	Xu W, Xu B, Zhao Y, Yang N, Liu C, Wen G and Zhang B: Wnt5a reverses the inhibitory effect of hyperoxia on transdifferentiation of alveolar epithelial type II cells to type I cells. J Physiol Biochem. 71:823–838. 2015. View Article : Google Scholar : PubMed/NCBI
23	Xu W, Zhao Y, Zhang B, Xu B, Yang Y, Wang Y and Liu C: Wnt3a mediates the inhibitory effect of hyperoxia on the trans-differentiation of AECIIs to AECIs. J Histochem Cytochem. 63:879–891. 2015. View Article : Google Scholar : PubMed/NCBI
24	Cohen JC, Larson JE, Killeen E, Love D and Takemaru K: CFTR and Wnt/beta-catenin signaling in lung development. BMC Dev Biol. 8:702008. View Article : Google Scholar : PubMed/NCBI
25	Freese JL, Pino D and Pleasure SJ: Wnt signaling in development and disease. Neurobiol Dis. 38:148–153. 2010. View Article : Google Scholar :
26	Katoh M: WNT signaling in stem cell biology and regenerative medicine. Curr Drug Targets. 9:565–570. 2008. View Article : Google Scholar : PubMed/NCBI
27	Aumiller V, Balsara N, Wilhelm J, Günther A and Königshoff M: WNT/β-Catenin signaling induces IL-1β expression by alveolar epithelial cells in pulmonary fibrosis. WNT signaling in stem cell biology and regenerative medicine. Am J Respir Cell Mol Biol. 49:96–104. 2013. View Article : Google Scholar : PubMed/NCBI
28	Jia L, Zhang Y, Ji Y, Xiong Y, Zhang W, Wen Y and Xu X: YAP balances the osteogenic and adipogenic differentiation of hPDLSCs in vitro partly through the Wnt/β-catenin signaling pathway. Biochem Biophys Res Commun. 518:154–160. 2019. View Article : Google Scholar : PubMed/NCBI
29	Imajo M, Miyatake K, Iimura A, Miyamoto A and Nishida E: A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling. EMBO J. 31:1109–1122. 2012. View Article : Google Scholar : PubMed/NCBI
30	Sun H, Choo-Wing R, Fan J, Leng L, Syed MA, Hare AA, Jorgensen WL, Bucala R and Bhandari V: Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia. Respir Res. 14:272013. View Article : Google Scholar : PubMed/NCBI
31	Jakkula M, Le Cras TD, Gebb S, Hirth KP, Tuder RM, Voelkel NF and Abman SH: Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol. 279:L600–L607. 2000. View Article : Google Scholar : PubMed/NCBI
32	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
33	Wang Y, Yu A and Yu FX: The Hippo pathway in tissue homeo-stasis and regeneration. Protein Cell. 8:349–359. 2017. View Article : Google Scholar : PubMed/NCBI
34	Cai J, Zhang N, Zheng Y, de Wilde RF, Maitra A and Pan D: The hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24:2383–2388. 2010. View Article : Google Scholar : PubMed/NCBI
35	Grijalva JL, Huizenga M, Mueller K, Rodriguez S, Brazzo J, Camargo F, Sadri-Vakili G and Vakili K: Dynamic alterations in hippo signaling pathway and YAP activation during liver regeneration. Am J Physiol Gastrointest Liver Physiol. 307:G196–G204. 2014. View Article : Google Scholar : PubMed/NCBI
36	Leslie CC, McCormick-Shannon K, Mason RJ and Shannon JM: Proliferation of rat alveolar epithelial cells in low density primary culture. Am J Respir Cell Mol Biol. 9:64–72. 1993. View Article : Google Scholar : PubMed/NCBI
37	Evans MJ, Cabral LJ, Stephens RJ and Freeman G: Renewal of alveolar epithelium in the rat following exposure to NO2. Am J Pathol. 70:175–198. 1973.PubMed/NCBI
38	Hu C, Sun J, Du J, Wen D, Lu H, Zhang H, Xue Y, Zhang A, Yang C, Zeng L and Jiang J: The hippo-YAP pathway regulates the proliferation of alveolar epithelial progenitors after acute lung injury. Cell Biol Int. 43:1174–1183. 2019. View Article : Google Scholar : PubMed/NCBI
39	Hou A, Fu J, Yang H, Zhu Y, Pan Y, Xu S and Xue X: Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats. Am J Physiol Lung Cell Mol Physiol. 308:L861–L872. 2015. View Article : Google Scholar : PubMed/NCBI
40	Zhou B, Flodby P, Luo J, Castillo DR, Liu Y, Yu FX, McConnell A, Varghese B, Li G, Chimge NO, et al: Claudin-18-Mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis. J Clin Invest. 128:970–984. 2018. View Article : Google Scholar : PubMed/NCBI
41	Zhao R, Fallon TR, Saladi SV, Pardo-Saganta A, Villoria J, Mou H, Vinarsky V, Gonzalez-Celeiro M, Nunna N, Hariri LP, et al: Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev Cell. 30:151–165. 2014. View Article : Google Scholar : PubMed/NCBI
42	Lin C, Yao E and Chuang PT: A conserved MST1/2-YAP axis mediates hippo signaling during lung growth. Dev Biol. 403:101–113. 2015. View Article : Google Scholar : PubMed/NCBI
43	Chung C, Kim T, Kim M, Kim M, Song H, Kim TS, Seo E, Lee SH, Kim H, Kim SK, et al: Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis. Proc Natl Acad Sci USA. 110:7732–7737. 2013. View Article : Google Scholar : PubMed/NCBI
44	Szymaniak AD, Mahoney JE, Cardoso WV and Varelas X: Crumbs3-Mediated polarity directs airway epithelial cell fate through the hippo pathway effector yap. Dev Cell. 34:283–296. 2015. View Article : Google Scholar : PubMed/NCBI
45	Volckaert T, Yuan T, Chao CM, Bell H, Sitaula A, Szimmtenings L, El Agha E, Chanda D, Majka S, Bellusci S, et al: Fgf10-Hippo epithelial-mesenchymal crosstalk maintains and recruits lung basal stem cells. Dev Cell. 43:48–59. 2017. View Article : Google Scholar : PubMed/NCBI
46	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
47	Wang Y, Huang C, Chintagari RN, Bhaskaran M, Weng T, Guo Y, Xiao X and Liu L: MiR-375 regulates rat alveolar epithelial cell trans-differentiation by inhibiting Wnt/β-catenin pathway. Nucleic Acids Res. 41:3833–3844. 2013. View Article : Google Scholar : PubMed/NCBI
48	Yang B, Sun H, Song F, Yu M, Wu Y and Wang J: YAP1 negatively regulates chondrocyte differentiation partly by activating the β-catenin signaling pathway. Int J Biochem Cell Biol. 87:104–113. 2017. View Article : Google Scholar : PubMed/NCBI
49	Takahashi A, Tsutsumi R, Kikuchi I, Obuse C, Saito Y, Seidi A, Karisch R, Fernandez M, Cho T, Ohnishi N, et al: SHP2 tyro-sine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Mol Cell. 43:45–56. 2011. View Article : Google Scholar : PubMed/NCBI
50	Tsutsumi R, Masoudi M, Takahashi A, Fujii Y, Hayashi T, Kikuchi I, Satou Y, Taira M and Hatakeyama M: YAP and TAZ, Hippo signaling targets, act as a rheostat for nuclear SHP2 function. Dev Cell. 26:658–665. 2013. View Article : Google Scholar : PubMed/NCBI
51	Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA, Sakuma R, Pawson T, Hunziker W, McNeill H, et al: The hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell. 18:579–591. 2010. View Article : Google Scholar : PubMed/NCBI
52	Clevers H, Loh KM and Nusse R: Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 346:12480122014. View Article : Google Scholar : PubMed/NCBI
53	Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL and Martin JF: Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 332:458–461. 2011. View Article : Google Scholar : PubMed/NCBI
54	Finn J, Sottoriva K, Pajcini KV, Kitajewski JK, Chen C, Zhang W, Malik AB and Liu Y: Dlk1-Mediated temporal regulation of notch signaling is required for differentiation of alveolar type II to type I cells during repair. Cell Rep. 26:2942–2954. 2019. View Article : Google Scholar : PubMed/NCBI
55	Gokey JJ, Sridharan A, Xu Y, Green J, Carraro G, Stripp BR, Perl AK and Whitsett JA: Active epithelial Hippo signaling in idiopathic pulmonary fibrosis. JCI Insight. 3:e987382018. View Article : Google Scholar :
56	Aspal M and Zemans RL: Mechanisms of ATII-to-ATI Cell Differentiation during lung regeneration. Int J Mol Sci. 21:31882020. View Article : Google Scholar :