Abstract
Mesenchymal stem cells (MSCs) have been applied in treating various diseases including myocardial infarction (MI) and achieved a bit of success; however, the decreased survival rate of MSCs after transplantation greatly limited the efficacy for cell therapy. How to improve the MSC survival rate in stem cell transplantation has undoubtedly become urgent and genetic engineering may be an ideal and feasible way. In this study, we explored the effects on MSCs survival and self-renewal by overexpression of integrin-linked kinase (ILK) in MSCs under hypoxic stimulation and aimed to reveal the molecular mechanisms from the point of paracrine function of MSCs. We first found that overexpression of ILK induced the expression and secretion of IL-6 increased significantly in MSCs under hypoxic stimulation, and the survival and self-renewal of MSCs exposed to hypoxia were enhanced after ILK overexpression. Then the activation of JAK2/STAT3 signaling was detected because of the increased IL-6, and an lncRNA, named lncTCF7, was upregulated remarkably, promoting the activation of Wnt pathway that was required for keeping cell viability and stemness of MSCs. Moreover, we further verified that inhibition of STAT3 signaling by WP1066 and silencing lncTCF7 expression eliminated the protective effects of ILK overexpression on cell survival and self-renewal of MSCs under hypoxic sitmulation. In conclusion, our results uncovered a novel function of ILK to promote MSC survival and self-renewal, suggesting more application potentials of MSC cell therapy on MI.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zomer HD, Vidane AS, Gonçalves NN, Ambrósio CE. Mesenchymal and induced pluripotent stem cells: general insights and clinical perspectives. Stem Cells Cloning. 2015;8:125–34.
D’souza N, Rossignoli F, Golinelli G, Grisendi G, Spano C, Candini O, et al. Mesenchymal stem/stromal cells as a delivery platform in cell and gene therapies. BMC Med. 2015;13:186.
Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiol Rev. 2016;96:1127–68.
Perico L, Morigi M, Rota C, Breno M, Mele C, Noris M, et al. Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat Commun. 2017;8:983.
Luk F, Carreras-Planella L, Korevaar SS, de Witte SFH, Borràs FE, Betjes MGH, et al. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function. Front Immunol. 2017;8:1042.
Karantalis V, Suncion-Loescher VY, Bagno L, Golpanian S, Wolf A, Sanina C, et al. Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. J Am Coll Cardiol. 2015;66:1990–9.
Natsumeda M, Florea V, Rieger AC, Tompkins BA, Banerjee MN, Golpanian S, et al. A combination of allogeneic stem cells promotes cardiac regeneration. J Am Coll Cardiol. 2017;70:2504–15.
Luger D, Lipinski MJ, Westman PC, Glover DK, Dimastromatteo J, Frias JC, et al. Intravenously delivered mesenchymal stem cells: systemic anti-inflammatory effects improve left ventricular dysfunction in acute myocardial infarction and ischemic cardiomyopathy. Circ Res. 2017;120:1598–613.
Kanelidis AJ, Premer C, Lopez J, Balkan W, Hare JM. Route of delivery modulates the efficacy of mesenchymal stem cell therapy for myocardial infarction: a meta-analysis of preclinical studies and clinical trials. Circ Res. 2017;120:1139–50.
He H, Zhao ZH, Han FS, Liu XH, Wang R, Zeng YJ. Overexpression of protein kinase C varepsilon improves retention and survival of transplanted mesenchymal stem cells in rat acute myocardial infarction. Cell Death Dis. 2016;7:e2056.
Blocki A, Beyer S, Dewavrin JY, Goralczyk A, Wang Y, Peh P, et al. Microcapsules engineered to support mesenchymal stem cell (MSC) survival and proliferation enable long-term retention of MSCs in infarcted myocardium. Biomaterials. 2015;53:12–24.
Hannigan GE, Coles JG, Dedhar S. Integrin-linked kinase at the heart of cardiac contractility, repair, and disease. Circ Res. 2007;100:1408–14.
Qin J, Wu C. a pseudokinase in the center stage of cell-matrix adhesion and signaling. Curr Opin Cell Biol. 2012;24:607–13.
Ding L, Dong L, Chen X, Zhang L, Xu X, Ferro A, et al. Increased expression of integrin-linked kinase attenuates left ventricular remodeling and improves cardiac function after myocardial infarction. Circulation. 2009;120:764–73.
Song SW, Chang W, Song BW, Song H, Lim S, Kim HJ, et al. Integrin-linked kinase is required in hypoxic mesenchymal stem cells for strengthening cell adhesion to ischemic myocardium. Stem Cells. 2009;27:1358–65.
Mao Q, Lin C, Gao J, Liang X, Gao W, Shen L, et al. Mesenchymal stem cells overexpressing integrin-linked kinase attenuate left ventricular remodeling and improve cardiac function after myocardial infarction. Mol Cell Biochem. 2014;397:203–14.
Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010;107:913–22.
Hatzistergos KE, Saur D, Seidler B, Balkan W, Breton M, Valasaki K, et al. Stimulatory effects of mesenchymal stem cells on cKit+ cardiac stem cells are mediated by SDF1/CXCR4 and SCF/cKit signaling pathways. Circ Res. 2016;119:921–30.
Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ, et al. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol. 2011;50:280–9.
Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo MT, et al. Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells. 2004;22:522–30.
Dreesen O, Brivanlou AH. Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev. 2007;3:7–17.
Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015;16:413–25.
Wu J, Zhang J, Shen B, Yin K, Xu J, Gao W, et al. Long noncoding RNA lncTCF7, induced by IL-6/STAT3 transactivation, promotes hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition. J Exp Clin Cancer Res. 2015;34:116.
Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004;109:1543–9.
Yang F, Wu R, Jiang Z, Chen J, Nan J, Su S, et al. Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation. Cell Death Dis. 2018;9:556.
Srivastava D, Yu S. Stretching to meet needs: integrin-linked kinase and the cardiac pump. Genes Dev. 2006;20:2327–31.
Mao Q, Lin CX, Liang XL, Gao JS, Xu B. Mesenchymal stem cells overexpressing integrin-linked kinase attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions. Mol Med Rep. 2013;7:1617–23.
Mu D, Zhang XL, Xie J, Yuan HH, Wang K, Huang W, et al. Intracoronary transplantation of mesenchymal stem cells with overexpressed integrin-linked kinase improves cardiac function in porcine myocardial infarction. Sci Rep. 2016;6:19155.
Hsu EC, Kulp SK, Huang HL, Tu HJ, Chao MW, Tseng YC, et al. Integrin-linked kinase as a novel molecular switch of the IL-6-NF-kappaB signaling loop in breast cancer. Carcinogenesis. 2016;37:430–42.
Hsu EC, Kulp SK, Huang HL, Tu HJ, Salunke SB, Sullivan NJ, et al. Function of integrin-linked kinase in modulating the stemness of IL-6-abundant breast cancer cells by regulating gamma-secretase-mediated Notch1 activation in caveolae. Neoplasia. 2015;17:497–508.
Wani AA, Jafarnejad SM, Zhou J, Li G. Integrin-linked kinase regulates melanoma angiogenesis by activating NF-kappaB/interleukin-6 signaling pathway. Oncogene. 2011;30:2778–88.
Wang X, Zhang Z, Yao C. Targeting integrin-linked kinase increases apoptosis and decreases invasion of myeloma cell lines and inhibits IL-6 and VEGF secretion from BMSCs. Med Oncol. 2011;28:1596–600.
Wu J, Wang D. Long noncoding RNA TCF7 promotes invasiveness and self-renewal of human non-small cell lung cancer cells. Hum Cell. 2017;30:23–29.
Li T, Zhu J, Wang X, Chen G, Sun L, Zuo S, et al. Long non-coding RNA lncTCF7 activates the Wnt/beta-catenin pathway to promote metastasis and invasion in colorectal cancer. Oncol Lett. 2017;14:7384–90.
Zeng B, Liu L, Wang S, Dai Z. ILK regulates MSCs survival and angiogenesis partially through AKT and mTOR signaling pathways. Acta Histochem. 2017;119:400–6.
Shabbir A, Zisa D, Lin H, Mastri M, Roloff G, Suzuki G, et al. Activation of host tissue trophic factors through JAK-STAT3 signaling: a mechanism of mesenchymal stem cell-mediated cardiac repair. Am J Physiol Heart Circ Physiol. 2010;299:H1428–38.
Yu SJ, Kim HJ, Lee ES, Park CG, Cho SJ, Jeon SH. beta-Catenin accumulation is associated with increased expression of Nanog protein and predicts maintenance of MSC self-renewal. Cell Transplant. 2017;26:365–77.
Acknowledgements
This work was supported by The General Program of Guangxi Natural Science Foundation (No. 2017GXNSFAA198214).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Mao, Q., Liang, XL., Wu, YF. et al. ILK promotes survival and self-renewal of hypoxic MSCs via the activation of lncTCF7-Wnt pathway induced by IL-6/STAT3 signaling. Gene Ther 26, 165–176 (2019). https://doi.org/10.1038/s41434-018-0055-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41434-018-0055-2
This article is cited by
-
Regulation Mechanisms and Maintenance Strategies of Stemness in Mesenchymal Stem Cells
Stem Cell Reviews and Reports (2024)
-
Differential expression of circular RNAs in interleukin 6-promoted osteogenic differentiation of human stem cells from apical papilla
Clinical Oral Investigations (2023)
-
Mechanobiological conditioning of mesenchymal stem cells for enhanced vascular regeneration
Nature Biomedical Engineering (2021)
-
Understanding the regulatory mechanisms of endometrial cells on activities of endometrial mesenchymal stem-like cells during menstruation
Stem Cell Research & Therapy (2020)
-
Improved therapeutics of modified mesenchymal stem cells: an update
Journal of Translational Medicine (2020)