Role of lincRNA‑p21 in the protective effect of macrophage inhibition factor against hypoxia/serum deprivation‑induced apoptosis in mesenchymal stem cells

Xia,Wenzheng; Zhuang,Lei; Hou,Meng

doi:10.3892/ijmm.2018.3767

Role of lincRNA‑p21 in the protective effect of macrophage inhibition factor against hypoxia/serum deprivation‑induced apoptosis in mesenchymal stem cells

Authors:
- Wenzheng Xia
- Lei Zhuang
- Meng Hou
View Affiliations

Affiliations: Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Hepatobiliary Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: July 12, 2018 https://doi.org/10.3892/ijmm.2018.3767
Pages: 2175-2184

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

Stem cell transplantation is a promising clinical strategy for curing ischemic cardiomyopathy. However, its efficacy is impaired by low cell survival following transplantation, partly caused by insufficient resistance of the transplanted stem cells to severe oxidative stress at the injury site. In the current study, it was demonstrated that the small‑molecule macrophage migration inhibitory factor (MIF) enhanced the defense of bone marrow‑derived mesenchymal stem cells (MSCs) against hypoxia/serum deprivation (SD)‑induced apoptosis in vitro. MIF significantly suppressed apoptosis and caspase family activities through inhibition of long intergenic noncoding (linc) RNA‑p21 to maintain activation of the Wnt/β‑catenin signaling pathway. The regulatory loop between MIF and the lincRNA‑p21‑Wnt/β‑catenin signaling pathway was identified to be associated with the inhibition of oxidative stress. The involvement of the lincRNA‑p21‑Wnt/β‑catenin signaling pathway in the effects of MIF in MSCs by overexpression of lincRNA‑p21and silencing β‑catenin using small interfering RNA was also demonstrated, both of which abolished the anti‑apoptotic and anti‑oxidative effects of MIF in MSCs under hypoxia/SD conditions. In conclusion, MIF protected MSCs from hypoxia/SD‑induced apoptosis by interacting with lincRNA‑p21, leading to activation of the downstream Wnt/β‑catenin signaling pathway and decreased oxidative stress. Thus, treatment with MIF may have important therapeutic implications in improving MSC survival and therapeutic efficiency.

View Figures

View References

1	Chareonthaitawee P, Gersh BJ, Araoz PA and Gibbons RJ: Revascularization in severe left ventricular dysfunction: The role of viability testing. J Am Coll Cardiol. 46:567–574. 2005. View Article : Google Scholar : PubMed/NCBI
2	Karantalis V, Suncion-Loescher VY, Bagno L, Golpanian S, Wolf A, Sanina C, Premer C, Kanelidis AJ, McCall F, Wang B, et al: Synergistic Effects of combined cell therapy for chronic ischemic cardiomyopathy. J Am Coll Cardiol. 66:1990–1999. 2015. View Article : Google Scholar : PubMed/NCBI
3	Natsumeda M, Florea V, Rieger AC, Tompkins BA, Banerjee MN, Golpanian S, Fritsch J, Landin AM, Kashikar ND, Karantalis V, et al: A combination of allogeneic stem cells promotes cardiac regeneration. J Am Coll Cardiol. 70:2504–2515. 2017. View Article : Google Scholar : PubMed/NCBI
4	Abdelwahid E, Kalvelyte A, Stulpinas A, de Carvalho KA, Guarita-Souza LC and Foldes G: Stem cell death and survival in heart regeneration and repair. Apoptosis. 21:252–268. 2016. View Article : Google Scholar
5	Golpanian S, Wolf A, Hatzistergos KE and Hare JM: Rebuilding the damaged heart: Mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiol Rev. 96:1127–1168. 2016. View Article : Google Scholar : PubMed/NCBI
6	Luedike P, Hendgen-Cotta UB, Sobierajski J, Totzeck M, Reeh M, Dewor M, Lue H, Krisp C, Wolters D, Kelm M, et al: Cardioprotection through S-nitros(yl)ation of macrophage migration inhibitory factor. Circulation. 125:1880–1889. 2012. View Article : Google Scholar : PubMed/NCBI
7	Calandra T and Roger T: Macrophage migration inhibitory factor: A regulator of innate immunity. Nat Rev Immunol. 3:791–800. 2003. View Article : Google Scholar : PubMed/NCBI
8	Qi D, Hu X, Wu X, Merk M, Leng L, Bucala R and Young LH: Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion. J Clin Invest. 119:3807–3816. 2009. View Article : Google Scholar : PubMed/NCBI
9	Zernecke A, Bernhagen J and Weber C: Macrophage migration inhibitory factor in cardiovascular disease. Circulation. 117:1594–1602. 2008. View Article : Google Scholar : PubMed/NCBI
10	Sun Q, Hao Q and Prasanth KV: Nuclear long noncoding RNAs: Key regulators of gene expression. Trends Genet. S0168-9525(17)30207-X. 2017.PubMed/NCBI
11	Liu C, Yang Z, Wu J, Zhang L, Lee S, Shin DJ, Tran M and Wang L: Long noncoding RNA H19 interacts with polypyrimidine tract-binding protein 1 to reprogram hepatic lipid homeostasis. Hepatology. 67:1768–1783. 2018. View Article : Google Scholar
12	Chew CL, Conos SA, Unal B and Tergaonkar V: Noncoding RNAs: Master regulators of inflammatory signaling. Trends Mol Med. 24:66–84. 2018. View Article : Google Scholar
13	Bao X, Wu H, Zhu X, Guo X, Hutchins AP, Luo Z, Song H, Chen Y, Lai K, Yin M, et al: The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters. Cell Res. 25:80–92. 2015. View Article : Google Scholar :
14	Yang N, Fu Y, Zhang H, Sima H, Zhu N and Yang G: LincRNA-p21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma. Oncotarget. 6:28151–28163. 2015.PubMed/NCBI
15	Yang W, Yu H, Shen Y, Liu Y, Yang Z and Sun T: MiR-146b-5p overexpression attenuates stemness and radioresistance of glioma stem cells by targeting HuR/lincRNA-p21/β-catenin pathway. Oncotarget. 7:41505–41526. 2016.PubMed/NCBI
16	Xia W, Zhuang L, Deng X and Hou M: Long noncoding RNA-p21 modulates cellular senescence via the Wnt/β-catenin signaling pathway in mesenchymal stem cells. Mol Med Rep. 16:7039–7047. 2017. View Article : Google Scholar : PubMed/NCBI
17	Yoshihisa Y, Rehman MU, Kondo T and Shimizu T: Role of macrophage migration inhibitory factor in heat-induced apoptosis in keratinocytes. Faseb J. 30:3870–3877. 2016. View Article : Google Scholar : PubMed/NCBI
18	Gammons M and Bienz M: Multiprotein complexes governing Wnt signal transduction. Curr Opin Cell Biol. 51:42–49. 2018. View Article : Google Scholar
19	Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S, Huarte M, Zhan M, Becker KG and Gorospe M: LincRNA-p21 suppresses target mRNA translation. Mol Cell. 47:648–655. 2012. View Article : Google Scholar : PubMed/NCBI
20	Yu F, Guo Y, Chen B, Shi L, Dong P, Zhou M and Zheng J: LincRNA-p21 inhibits the Wnt/β-catenin pathway in activated hepatic stellate cells via sponging MicroRNA-17-5p. Cell Physiol Biochem. 41:1970–1980. 2017. View Article : Google Scholar
21	Zhu W, Chen J, Cong X, Hu S and Chen X: Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells. 24:416–425. 2006. View Article : Google Scholar
22	Gore Y, Starlets D, Maharshak N, Becker-Herman S, Kaneyuki U, Leng L, Bucala R and Shachar I: Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex. J Biol Chem. 283:2784–2792. 2008. View Article : Google Scholar
23	Liu Y, Xiong Y, Xing F, Gao H, Wang X, He L, Ren C, Liu L, So KF and Xiao J: Precise regulation of miR-210 is critical for the cellular homeostasis maintenance and transplantation efficacy enhancement of mesenchymal stem cells in acute liver failure therapy. Cell Transplant. 26:805–820. 2017. View Article : Google Scholar :
24	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
25	Xia W, Xie C, Jiang M and Hou M: Improved survival of mesen-chymal stem cells by macrophage migration inhibitory factor. Mol Cell Biochem. 404:11–24. 2015. View Article : Google Scholar : PubMed/NCBI
26	Shen Y, Liu Y, Sun T and Yang W: LincRNA-p21 knockdown enhances radiosensitivity of hypoxic tumor cells by reducing autophagy through HIF-1/Akt/mTOR/P70S6K pathway. Exp Cell Res. 358:188–198. 2017. View Article : Google Scholar : PubMed/NCBI
27	Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, Zhao L, Vatan L, Shao I, Szeliga W, et al: Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. 18:1332–1341. 2017. View Article : Google Scholar : PubMed/NCBI
28	Nakamura Y, Wang X, Xu C, Asakura A, Yoshiyama M, From AH and Zhang J: Xenotransplantation of long-term-cultured swine bone marrow-derived mesenchymal stem cells. Stem Cells. 25:612–620. 2007. View Article : Google Scholar
29	Amado LC, Schuleri KH, Saliaris AP, Boyle AJ, Helm R, Oskouei B, Centola M, Eneboe V, Young R, Lima JA, et al: Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol. 48:2116–2124. 2006. View Article : Google Scholar : PubMed/NCBI
30	Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, et al: A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 54:2277–2286. 2009. View Article : Google Scholar : PubMed/NCBI
31	Ye L, Zhang P, Duval S, Su L, Xiong Q and Zhang J: Thymosin β4 increases the potency of transplanted mesenchymal stem cells for myocardial repair. Circulation. 128(11 Suppl 1): S32–S41. 2013. View Article : Google Scholar : PubMed/NCBI
32	Takahashi M, Nishihira J, Katsuki T, Kobayashi E, Ikeda U and Shimada K: Elevation of plasma levels of macrophage migration inhibitory factor in patients with acute myocardial infarction. Am J Cardiol. 89:248–249. 2002. View Article : Google Scholar : PubMed/NCBI
33	Yu CM, Lai KW, Chen YX, Huang XR and Lan HY: Expression of macrophage migration inhibitory factor in acute ischemic myocardial injury. J Histochem Cytochem. 51:625–631. 2003. View Article : Google Scholar : PubMed/NCBI
34	Chagnon F, Metz CN, Bucala R and Lesur O: Endotoxin-induced myocardial dysfunction: Effects of macrophage migration inhibitory factor neutralization. Circ Res. 96:1095–1102. 2005. View Article : Google Scholar : PubMed/NCBI
35	Wang J, Tong C, Yan X, Yeung E, Gandavadi S, Hare AA, Du X, Chen Y, Xiong H, Ma C, et al: Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction. Circulation. 128:225–236. 2013. View Article : Google Scholar : PubMed/NCBI
36	Ulitsky I and Bartel DP: lincRNAs: Genomics, evolution, and mechanisms. Cell. 154:26–46. 2013. View Article : Google Scholar : PubMed/NCBI
37	Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, Payumo AY, Peres-da-Silva A, Broz DK, Baum R, et al: An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet. 48:1370–1376. 2016. View Article : Google Scholar : PubMed/NCBI
38	Liu X, Xiao ZD, Zhang J, Lee SW, Wang W, Lee H, Zhuang L, Chen J and Lin HK: LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nat Cell Biol. 18:431–442. 2016. View Article : Google Scholar : PubMed/NCBI
39	Chen S, Liang H, Yang H, Zhou K, Xu L, Liu J, Lai B, Song L, Luo H, Peng J, et al: LincRNa-p21: Function and mechanism in cancer. Med Oncol. 34:982017. View Article : Google Scholar : PubMed/NCBI
40	Lettini G, Sisinni L, Condelli V, Matassa DS, Simeon V, Maddalena F, Gemei M, Lopes E, Vita G, Del Vecchio L, et al: TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma. Cell Death Differ. 23:1792–1803. 2016. View Article : Google Scholar : PubMed/NCBI
41	Wang J, Lei ZJ, Guo Y, Wang T, Qin ZY, Xiao HL, Fan LL, Chen DF, Bian XW, Liu J and Wang B: miRNA-regulated delivery of lincRNA-p21 suppresses β-catenin signaling and tumorigenicity of colorectal cancer stem cells. Oncotarget. 6:37852–37870. 2015.PubMed/NCBI
42	Zhang X, Chen L, Wang Y, Ding Y, Peng Z, Duan L, Ju G, Ren Y and Wang X: Macrophage migration inhibitory factor promotes proliferation and neuronal differentiation of neural stem/precursor cells through Wnt/β-catenin signal pathway. Int J Biol Sci. 9:1108–1120. 2013. View Article : Google Scholar :
43	Matsushima S, Kuroda J, Zhai P, Liu T, Ikeda S, Nagarajan N, Oka S, Yokota T, Kinugawa S, Hsu CP, et al: Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. J Clin Invest. 126:3403–3416. 2016. View Article : Google Scholar : PubMed/NCBI
44	Han YS, Lee JH, Jung JS, Noh H, Baek MJ, Ryu JM, Yoon YM, Han HJ and Lee SH: Fucoidan protects mesenchymal stem cells against oxidative stress and enhances vascular regeneration in a murine hindlimb ischemia model. Int J Cardiol. 198:187–195. 2015. View Article : Google Scholar : PubMed/NCBI
45	Zhang D, Lee H, Haspel JA and Jin Y: Long noncoding RNA FOXD3-AS1 regulates oxidative stress-induced apoptosis via sponging microRNA-150. FASEB J. 31:4472–4481. 2017. View Article : Google Scholar : PubMed/NCBI
46	Xu X, Bucala R and Ren J: Macrophage migration inhibitory factor deficiency augments doxorubicin-induced cardiomyopathy. J Am Heart Assoc. 2:e0004392013. View Article : Google Scholar : PubMed/NCBI