The transplantation of Akt-overexpressing amniotic fluid-derived mesenchymal stem cells protects the heart against ischemia-reperfusion injury in rabbits

Wang,Yan; Li,Yigang; Song,Lei; Li,Yanyan; Jiang,Shan; Zhang,Song

doi:10.3892/mmr.2016.5212

The transplantation of Akt-overexpressing amniotic fluid-derived mesenchymal stem cells protects the heart against ischemia-reperfusion injury in rabbits

Authors:
- Yan Wang
- Yigang Li
- Lei Song
- Yanyan Li
- Shan Jiang
- Song Zhang
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Affiliations: Department of Geriatrics, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China, Department of Cardiovascular Diseases, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
Published online on: May 5, 2016 https://doi.org/10.3892/mmr.2016.5212
Pages: 234-242
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Amniotic fluid-derived mesenchymal stem cells (AFMSCs) are an attractive cell source for applications in regenerative medicine, due to characteristics such as proliferative capacity and multipotency. In addition, Akt, a serine‑threonine kinase, maintains stem cells by promoting viability and proliferation. Whether the transplantation of Akt-overexpressing AFMSCs protects the heart against ischemia‑reperfusion (I/R) injury has yet to be elucidated. Accordingly, the Akt gene was overexpressed in AFMSCs using lentiviral transduction, and Akt‑AFMSCs were transplanted into the ischemic myocardium of rabbits prior to reperfusion. Any protective effects resulting from this procedure were subsequently sought after three weeks later. A histological examination revealed that there was a decrease in intramyocardial inflammation and ultrastructural damage, and an increase in capillary density and in the levels of GATA binding protein 4, connexin 43 and cardiac troponin T in the Akt‑AFMSC group compared with the control group. A significant decrease in cardiomyocyte apoptosis, accompanying an increase in phosphorylated Akt and B‑cell lymphoma 2 (Bcl-2) and a decrease in caspase‑3, was also observed. Furthermore, the left ventricular function was markedly augmented in the Akt‑AFMSC group compared with the control group. These observations suggested that the protective effect of AFMSCs may be due to the delivery of secreted cytokines, promotion of neoangiogenesis, prevention of cardiomyocyte apoptosis, transdifferentiation into cardiomyocytes and promotion of the viability of AFMSCs, which are assisted by Akt gene modification. Taken together, the results of the present study have indicated that transplantation of Akt-AFMSCs is able to alleviate myocardial I/R injury and improve cardiac function.

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1	Angoulvant D, Ivanes F, Ferrera R, Matthews PG, Nataf S and Ovize M: Mesenchymal stem cell conditioned media attenuates in vitro and ex vivo myocardial reperfusion injury. J Heart Lung Transplant. 30:95–102. 2011. View Article : Google Scholar
2	Preda MB, Rønningen T, Burlacu A, Simionescu M, Moskaug JØ and Valen G: Remote transplantation of mesenchymal stem cells protects the heart against ischemia-reperfusion injury. Stem Cells. 32:2123–2134. 2014. View Article : Google Scholar : PubMed/NCBI
3	Wang Y, Abarbanell AM, Herrmann JL, Weil BR, Manukyan MC, Poynter JA and Meldrum DR: TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection. PloS One. 5:e142062010. View Article : Google Scholar : PubMed/NCBI
4	Dexheimer V, Mueller S, Braatz F and Richter W: Reduced reactivation from dormancy but maintained lineage choice of human mesenchymal stem cells with donor age. PloS One. 6:e229802011. View Article : Google Scholar : PubMed/NCBI
5	Kanawa M, Igarashi A, Ronald VS, Higashi Y, Kurihara H, Sugiyama M, Saskianti T, Pan H and Kato Y: Age-dependent decrease in the chondrogenic potential of human bone marrow mesenchymal stromal cells expanded with fibroblast growth factor-2. Cytotherapy. 15:1062–1072. 2013. View Article : Google Scholar : PubMed/NCBI
6	Maioli M, Contini G, Santaniello S, Bandiera P, Pigliaru G, Sanna R, Rinaldi S, Delitala AP, Montella A, Bagella L and Ventura C: Amniotic fluid stem cells morph into a cardiovascular lineage: Analysis of a chemically induced cardiac and vascular commitment. Drug Des Devel Ther. 7:1063–1073. 2013.PubMed/NCBI
7	Rennie K, Gruslin A, Hengstschläger M, Pei D, Cai J, Nikaido T and Bani-Yaghoub M: Applications of amniotic membrane and fluid in stem cell biology and regenerative medicine. Stem Cells Int. 2012:7215382012. View Article : Google Scholar : PubMed/NCBI
8	Cheng AS and Yau TM: Paracrine effects of cell transplantation: Strategies to augment the efficacy of cell therapies. Semin Thorac Cardiovasc Surg. 20:94–101. 2008. View Article : Google Scholar : PubMed/NCBI
9	Zhang M, Methot D, Poppa V, Fujio Y, Walsh K and Murry CE: Cardiomyocyte grafting for cardiac repair: Graft cell death and anti-death strategies. J Mol Cell Cardiol. 33:907–921. 2001. View Article : Google Scholar : PubMed/NCBI
10	Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL and Robbins RC: Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 428:668–673. 2004. View Article : Google Scholar : PubMed/NCBI
11	Hammerman PS, Fox CJ, Birnbaum MJ and Thompson CB: Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood. 105:4477–4483. 2005. View Article : Google Scholar : PubMed/NCBI
12	Kim SJ, Cheon SH, Yoo SJ, Kwon J, Park JH, Kim CG, Rhee K, You S, Lee JY, Roh SI and Yoon HS: Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self-renewal in human embryonic stem cells. FEBS Lett. 579:534–540. 2005. View Article : Google Scholar : PubMed/NCBI
13	Catalucci D and Condorelli G: Effects of Akt on cardiac myocytes: Location counts. Circ Res. 99:339–341. 2006. View Article : Google Scholar : PubMed/NCBI
14	Lim SY, Kim YS, Ahn Y, Jeong MH, Hong MH, Joo SY, Nam KI, Cho JG, Kang PM and Park JC: The effects of mesenchymal stem cells transduced with Akt in a porcine myocardial infarction model. Cardiovasc Res. 70:530–542. 2006. View Article : Google Scholar : PubMed/NCBI
15	Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS and Dzau VJ: Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 9:1195–1201. 2003. View Article : Google Scholar : PubMed/NCBI
16	Yu YS, Shen ZY, Ye WX, Huang HY, Hua F, Chen YH, Chen K, Lao WJ and Tao L: AKT-modified autologous intracoronary mesenchymal stem cells prevent remodeling and repair in swine infarcted myocardium. Chin Med J (Engl). 123:1702–1708. 2010.
17	Fei X, Jiang S, Zhang S, Li Y, Ge J, He B, Goldstein S and Ruiz G: Isolation, culture and identification of amniotic fluid-derived mesenchymal stem cells. Cell Biochem Biophys. 67:689–694. 2013. View Article : Google Scholar : PubMed/NCBI
18	Zhang S, Zhang M, Goldstein S, Li Y, Ge J, He B and Ruiz G: The effect of c-fos on acute myocardial infarction and the significance of metoprolol intervention in a rat model. Cell Biochem Biophys. 65:249–255. 2013. View Article : Google Scholar
19	Zhang S, Liu X, Goldstein S, Li Y, Ge J, He B, Fei X, Wang Z and Ruiz G: Role of the JAK/STAT signaling pathway in the pathogenesis of acute myocardial infarction in rats and its effect on NF-κB expression. Mol Med Rep. 7:93–98. 2013.
20	Chen C, Xu Y and Song Y: IGF-1 gene-modified muscle-derived stem cells are resistant to oxidative stress via enhanced activation of IGF-1R/PI3K/AKT signaling and secretion of VEGF. Mol Cell Biochem. 386:167–175. 2014. View Article : Google Scholar
21	Takashima S, Tempel D and Duckers HJ: Current outlook of cardiac stem cell therapy towards a clinical application. Heart. 99:1772–1784. 2013. View Article : Google Scholar : PubMed/NCBI
22	Kunisaki SM, Fuchs JR, Steigman SA and Fauza DO: A comparative analysis of cartilage engineered from different perinatal mesenchymal progenitor cells. Tissue Eng. 13:2633–2644. 2007. View Article : Google Scholar : PubMed/NCBI
23	Kolambkar YM, Peister A, Soker S, Atala A and Guldberg RE: Chondrogenic differentiation of amniotic fluid-derived stem cells. J Mol Histol. 38:405–413. 2007. View Article : Google Scholar : PubMed/NCBI
24	Lanfranchi A, Porta F and Chirico G: Stem cells and the frontiers of neonatology. Early Hum Dev. 85(Suppl 10): S15–S18. 2009. View Article : Google Scholar : PubMed/NCBI
25	Davydova DA: Stem cells in human amniotic fluid. Izv Akad Nauk Ser Biol. 517–526. 2010.In Russian.
26	Sessarego N, Parodi A, Podestà M, Benvenuto F, Mogni M, Raviolo V, Lituania M, Kunkl A, Ferlazzo G, Bricarelli FD, et al: Multipotent mesenchymal stromal cells from amniotic fluid: Solid perspectives for clinical application. Haematologica. 93:339–346. 2008. View Article : Google Scholar : PubMed/NCBI
27	Zhou J, Wang D, Liang T, Guo Q and Zhang G: Amniotic fluid-derived mesenchymal stem cells: Characteristics and therapeutic applications. Arch Gynecol Obstet. 290:223–231. 2014. View Article : Google Scholar : PubMed/NCBI
28	Baulier E, Favreau F, Le Corf A, Jayle C, Schneider F, Goujon JM, Feraud O, Bennaceur-Griscelli A, Hauet T and Turhan AG: Amniotic fluid-derived mesenchymal stem cells prevent fibrosis and preserve renal function in a preclinical porcine model of kidney transplantation. Stem Cells Transl Med. 3:809–820. 2014. View Article : Google Scholar : PubMed/NCBI
29	Skardal A, Mack D, Kapetanovic E, Atala A, Jackson JD, Yoo J and Soker S: Bioprinted amniotic fluid-derived stem cells accelerate healing of large skin wounds. Stem Cells Transl Med. 1:792–802. 2012. View Article : Google Scholar : PubMed/NCBI
30	Zheng YB, Zhang XH, Huang ZL, Lin CS, Lai J, Gu YR, Lin BL, Xie DY, Xie SB, Peng L and Gao ZL: Amniotic-fluid-derived mesenchymal stem cells overexpressing interleukin-1 receptor antagonist improve fulminant hepatic failure. PloS One. 7:e413922012. View Article : Google Scholar : PubMed/NCBI
31	Villani V, Milanesi A, Sedrakyan S, Da Sacco S, Angelow S, Conconi MT, Di Liddo R, De Filippo R and Perin L: Amniotic fluid stem cells prevent β-cell injury. Cytotherapy. 16:41–55. 2014. View Article : Google Scholar
32	Yeh YC, Wei HJ, Lee WY, Yu CL, Chang Y, Hsu LW, Chung MF, Tsai MS, Hwang SM and Sung HW: Cellular cardiomyoplasty with human amniotic fluid stem cells: In vitro and in vivo studies. Tissue Eng Part A. 16:1925–1936. 2010. View Article : Google Scholar : PubMed/NCBI
33	Bollini S, Pozzobon M, Nobles M, Riegler J, Dong X, Piccoli M, Chiavegato A, Price AN, Ghionzoli M, Cheung KK, et al: In vitro and in vivo cardiomyogenic differentiation of amniotic fluid stem cells. Stem Cell Rev. 7:364–380. 2011. View Article : Google Scholar
34	Lee WY, Wei HJ, Lin WW, Yeh YC, Hwang SM, Wang JJ, Tsai MS, Chang Y and Sung HW: Enhancement of cell retention and functional benefits in myocardial infarction using human amniotic-fluid stem-cell bodies enriched with endogenous ECM. Biomaterials. 32:5558–5567. 2011. View Article : Google Scholar : PubMed/NCBI
35	Murphy E and Steenbergen C: Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 88:581–609. 2008. View Article : Google Scholar : PubMed/NCBI
36	Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS and Dzau VJ: Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20:661–669. 2006. View Article : Google Scholar : PubMed/NCBI
37	Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, Purushothaman S, Galuppo V, Iaconetti C, Waring CD, et al: Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol. 58:977–986. 2011. View Article : Google Scholar : PubMed/NCBI