In Vivo Combinatory Gene Therapy Synergistically Promotes Cardiac Function and Vascular Regeneration Following Myocardial Infarction

Overview

Journal J Tissue Eng

Date 2022 Jan 10

PMID 35003614

Authors

Sunghun Lee

Bong-Woo Park

Yong Jin Lee

Kiwon Ban

Hun-Jun Park

Affiliations

Soon will be listed here.

Abstract

Since myocardial infarction (MI) excessively damage the myocardium and blood vessels, the therapeutic approach for treating MI hearts should simultaneously target these two major components in the heart to achieve comprehensive cardiac repair. Here, we investigated a combinatory platform of ETV2 and Gata4, Mef2c and Tbx5 (GMT) transcription factors to develop a strategy that can rejuvenate both myocardium and vasculatures together in MI hearts. Previously ETV2 demonstrated significant effects on neovascularization and GMT was known to directly reprogram cardiac fibroblasts into cardiomyocytes under in vivo condition. Subsequently, intramyocardial delivery of a combination of retroviral GMT and adenoviral ETV2 particles into the rat MI hearts significantly increased viable myocardium area, capillary density compared to ETV2 or GMT only treated hearts, leading to improved heart function and reduced scar formation. These results demonstrate that this combinatorial gene therapy can be a promising approach to enhance the cardiac repair in MI hearts.

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References

Passier R, Mummery C . Getting to the heart of the matter: direct reprogramming to cardiomyocytes. Cell Stem Cell. 2010; 7(2):139-41. DOI: 10.1016/j.stem.2010.07.004. View

Gerber Y, Weston S, Enriquez-Sarano M, Berardi C, Chamberlain A, Manemann S . Mortality Associated With Heart Failure After Myocardial Infarction: A Contemporary Community Perspective. Circ Heart Fail. 2015; 9(1):e002460. PMC: 4692179. DOI: 10.1161/CIRCHEARTFAILURE.115.002460. View

Margariti A, Winkler B, Karamariti E, Zampetaki A, Tsai T, Baban D . Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels. Proc Natl Acad Sci U S A. 2012; 109(34):13793-8. PMC: 3427074. DOI: 10.1073/pnas.1205526109. View

Dwenger M, Kowalski W, Ye F, Yuan F, Tinney J, Setozaki S . Chronic optical pacing conditioning of h-iPSC engineered cardiac tissues. J Tissue Eng. 2019; 10:2041731419841748. PMC: 6472158. DOI: 10.1177/2041731419841748. View

Wei G, Srinivasan R, Cantemir-Stone C, Sharma S, Santhanam R, Weinstein M . Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood. 2009; 114(5):1123-30. PMC: 2721789. DOI: 10.1182/blood-2009-03-211391. View

Ali S, Hippenmeyer S, Saadat L, Luo L, Weissman I, Ardehali R . Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proc Natl Acad Sci U S A. 2014; 111(24):8850-5. PMC: 4066522. DOI: 10.1073/pnas.1408233111. View

Singh R, Knowles J, Kim H . Advances in nanoparticle development for improved therapeutics delivery: nanoscale topographical aspect. J Tissue Eng. 2019; 10:2041731419877528. PMC: 6749784. DOI: 10.1177/2041731419877528. View

Sekiya S, Suzuki A . Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature. 2011; 475(7356):390-3. DOI: 10.1038/nature10263. View

Song K, Nam Y, Luo X, Qi X, Tan W, Huang G . Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012; 485(7400):599-604. PMC: 3367390. DOI: 10.1038/nature11139. View

10.

Pham V, Lawson N, Mugford J, Dye L, Castranova D, Lo B . Combinatorial function of ETS transcription factors in the developing vasculature. Dev Biol. 2006; 303(2):772-83. PMC: 1859867. DOI: 10.1016/j.ydbio.2006.10.030. View

11.

Lee S, Lee D, Park B, Kim R, Hoang A, Woo S . In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction. Exp Mol Med. 2019; 51(2):1-14. PMC: 6372609. DOI: 10.1038/s12276-019-0206-6. View

12.

Vierbuchen T, Ostermeier A, Pang Z, Kokubu Y, Sudhof T, Wernig M . Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010; 463(7284):1035-41. PMC: 2829121. DOI: 10.1038/nature08797. View

13.

Grieger J, Choi V, Samulski R . Production and characterization of adeno-associated viral vectors. Nat Protoc. 2007; 1(3):1412-28. DOI: 10.1038/nprot.2006.207. View

14.

Protze S, Khattak S, Poulet C, Lindemann D, Tanaka E, Ravens U . A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte-like cells. J Mol Cell Cardiol. 2012; 53(3):323-32. DOI: 10.1016/j.yjmcc.2012.04.010. View

15.

Lee J, Lee M, Lim Y, Knowles J, Kim H . Auditory disorders and future therapies with delivery systems. J Tissue Eng. 2018; 9:2041731418808455. PMC: 6207966. DOI: 10.1177/2041731418808455. View

16.

Park C, Lee T, Bhang S, Liu F, Nakamura R, Oladipupo S . Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. Arterioscler Thromb Vasc Biol. 2015; 36(1):86-96. PMC: 4690812. DOI: 10.1161/ATVBAHA.115.306430. View

17.

Park S, Kim R, Park B, Lee S, Choi S, Park J . Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction. Nat Commun. 2019; 10(1):3123. PMC: 6635499. DOI: 10.1038/s41467-019-11091-2. View

18.

Lee D, Park C, Lee H, Lugus J, Hyung Kim S, Arentson E . ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell. 2008; 2(5):497-507. PMC: 2683414. DOI: 10.1016/j.stem.2008.03.008. View

19.

Kelaini S, Cochrane A, Margariti A . Direct reprogramming of adult cells: avoiding the pluripotent state. Stem Cells Cloning. 2014; 7:19-29. PMC: 3931695. DOI: 10.2147/SCCAA.S38006. View

20.

Lee S, Park C, Han J, Kim J, Cho K, Kim E . Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2. Circ Res. 2016; 120(5):848-861. PMC: 5336520. DOI: 10.1161/CIRCRESAHA.116.309833. View