Enhanced human adipose-derived stem cells with VEGFA and bFGF mRNA promote stable vascular regeneration and improve cardiac function following myocardial infarction

Abstract

	•ModRNAs-transfected hADSCs exhibit pulsed and transient expression, enabling efficient production of functional VEGFA and bFGF proteins.
	•Intracardiac injection of these engineered hADSCs leads to the enhancement of cardiac function and the improvement of electrical conduction.
	•The hADSCsdual mainly exerts its effect on myocardial infarction by promoting stable vascular regeneration and suppressing cell apoptosis.

Keywords

bFGF / cell therapy / human adipose-derived stem cell / modRNA / myocardial infarction / VEGF

References

[1] Samsky MD, Morrow DA, Proudfoot AG, et al. Cardiogenic shock after acute myocardial infarction: a review. Jama. 2021;326(18):1840-1850.

[2] Peet C, Ivetic A, Bromage DI, et al. Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc Res. 2020;116(6):1101-1112.

[3] Barrère-Lemaire S, Vincent A, Jorgensen C, et al. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev. 2024;104(2):659-725.

[4] Ala M. The beneficial effects of mesenchymal stem cells and their exosomes on myocardial infarction and critical considerations for enhancing their efficacy. Ageing Res Rev. 2023;89:101980.

[5] Zhang R, Yu J, Zhang N, et al. Bone marrow mesenchymal stem cells transfer in patients with ST-segment elevation myocardial infarction: single-blind, multicenter, randomized controlled trial. Stem Cell Res Ther. 2021;12(1):33.

[6] Bacakova L, Zarubova J, Travnickova M, et al. Stem cells: their source, potency and use in regenerative therapies with focus on adipose-derived stem cells – a review. Biotechnol Adv. 2018;36(4):1111-1126.

[7] Mazini L, Rochette L, Admou B, et al. Hopes and limits of adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) in wound healing. Int J Mol Sci 2020;21(4).

[8] Al-Ghadban S, Bunnell BA. Adipose tissue-derived stem cells: immunomodulatory effects and therapeutic potential. Physiology (Bethesda). 2020;35(2):125-133.

[9] Zhao L, Johnson T, Liu D. Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. Stem Cell Res Ther. 2017;8(1):125.

[10] Raziyeva K, Smagulova A, Kim Y, et al. Preconditioned and genetically modified stem cells for myocardial infarction treatment. Int J Mol Sci 2020;21(19).

[11] Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet. 2024;403(10432):1192-1204.

[12] Pardi N, Hogan MJ, Weissman D. Recent advances in mRNA vaccine technology. Curr Opin Immunol. 2020;65:14-20.

[13] Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603-2615.

[14] Yu Z, Witman N, Wang W, et al. Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia. J Control Release. 2019;310:103-114.

[15] Wu H, Peng Z, Xu Y, et al. Engineered adipose-derived stem cells with IGF-1-modified mRNA ameliorates osteoarthritis development. Stem Cell Res Ther. 2022;13(1):19.

[16] Ai X, Yan B, Witman N, et al. Transient secretion of VEGF protein from transplanted hiPSC-CMs enhances engraftment and improves rat heart function post MI. Mol Ther. 2023;31(1):211-229.

[17] Yu F, Gong D, Yan D, et al. Enhanced adipose-derived stem cells with IGF-1-modified mRNA promote wound healing following corneal injury. Mol Ther. 2023;31(8):2454-2471.

[18] Zangi L, Lui KO, von Gise A, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol. 2013;31(10):898-907.

[19] Sultana N, Magadum A, Hadas Y, et al. Optimizing cardiac delivery of modified mRNA. Mol Ther. 2017;25(6):1306-1315.

[20] Presta M, Andrés G, Leali D, et al. Inflammatory cells and chemokines sustain FGF2-induced angiogenesis. Eur Cytokine Netw. 2009;20(2):39-50.

[21] Lazarous DF, Shou M, Scheinowitz M, et al. Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation. 1996;94(5):1074-1082.

[22] Lazarous DF, Scheinowitz M, Shou M, et al. Effects of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart. Circulation. 1995;91(1):145-153.

[23] Ye G, Fu Q, Jiang L, et al. Vascular smooth muscle cells activate PI3K/Akt pathway to attenuate myocardial ischemia/reperfusion-induced apoptosis and autophagy by secreting bFGF. Biomed Pharmacother. 2018;107:1779-1785.

[24] Rao Z, Shen D, Chen J, et al. Basic fibroblast growth factor attenuates injury in myocardial infarction by enhancing hypoxia-inducible factor-1 alpha accumulation. Front Pharmacol. 2020;11:1193.

[25] Luo Z, Bian Y, Zheng R, et al. Combination of chemically modified SDF-1α mRNA and small skin improves wound healing in diabetic rats with full-thickness skin defects. Cell Prolif. 2022;55(12):e13318.

[26] Yu F, Witman N, Yan D, et al. Human adipose-derived stem cells enriched with VEGF-modified mRNA promote angiogenesis and long-term graft survival in a fat graft transplantation model. Stem Cell Res Ther. 2020;11(1):490.

[27] Jiang L, Yang A, Li X, et al. Down-regulation of VCAM-1 in bone mesenchymal stem cells reduces inflammatory responses and apoptosis to improve cardiac function in rat with myocardial infarction. Int Immunopharmacol 2021;101(Pt A):108180.

[28] Rigol M, Solanes N, Roura S, et al. Allogeneic adipose stem cell therapy in acute myocardial infarction. Eur J Clin Invest. 2014;44(1):83-92.

[29] Valina C, Pinkernell K, Song YH, et al. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur Heart J. 2007;28(21):2667-2677.

[30] Yu LH, Kim MH, Park TH, et al. Improvement of cardiac function and remodeling by transplanting adipose tissue-derived stromal cells into a mouse model of acute myocardial infarction. Int J Cardiol. 2010;139(2):166-172.

[31] Zhang Q, Wang L, Wang S, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther. 2022;7(1):78.

[32] Shi Y, Wang Y, Li Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14(8):493-507.

[33] Bunnell BA. Adipose tissue-derived mesenchymal stem cells. Cells 2021;10(12).

[34] Żak MM, Gkontra P, Clemente C, et al. Sequential bone-marrow cell delivery of VEGFA/S1P improves vascularization and limits adverse cardiac remodeling after myocardial infarction in mice. Hum Gene Ther. 2019;30(7):893-905.

[35] Oduk Y, Zhu W, Kannappan R, et al. VEGF nanoparticles repair the heart after myocardial infarction. Am J Physiol Heart Circ Physiol. 2018;314(2):H278-h284.

[36] Sarkar N, Rück A, Källner G, et al. Effects of intramyocardial injection of phVEGF-A165 as sole therapy in patients with refractory coronary artery disease–12-month follow-up: angiogenic gene therapy. J Intern Med. 2001;250(5):373-381.

[37] Symes JF, Losordo DW, Vale PR, et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg. 1999;68(3):830-836; discussion 836–837.

[38] Lederle W, Linde N, Heusel J, et al. Platelet-derived growth factor-B normalizes micromorphology and vessel function in vascular endothelial growth factor-A-induced squamous cell carcinomas. Am J Pathol. 2010;176(2):981-994.

[39] Nagy JA, Benjamin L, Zeng H, et al. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis. 2008;11(2):109-119.

[40] Zhang X, Kang X, Jin L, et al. Stimulation of wound healing using bioinspired hydrogels with basic fibroblast growth factor (bFGF). Int J Nanomedicine. 2018;13:3897-3906.

[41] Chen M, Bao L, Zhao M, et al. Progress in research on the role of FGF in the formation and treatment of corneal neovascularization. Front Pharmacol. 2020;11:111.

[42] Fan Z, Xu Z, Niu H, et al. Spatiotemporal delivery of basic fibroblast growth factor to directly and simultaneously attenuate cardiac fibrosis and promote cardiac tissue vascularization following myocardial infarction. J Control Release 2019; 311-312:233-244.

[43] Rakue H, Nakajima H, Katoh T, et al. Low-dose basic fibroblast growth factor and vascular endothelial growth factor for angiogenesis in canine acute hindlimb insufficiency. Jpn Circ J. 1998;62(12):933-939.

[44] Kukuła K, Chojnowska L, Dąbrowski M, et al. Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD). Am Heart J. 2011;161(3):581-589.

[45] Kastrup J, Jørgensen E, Rück A, et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol. 2005;45(7):982-988.

[46] Gyöngyösi M, Khorsand A, Zamini S, et al. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation 2005;112(9 Suppl):I157-165.

[47] McCormick K, Moreno Herrero J, Haas H, et al. Optimizing the delivery of mRNA to mesenchymal stem cells for tissue engineering applications. Mol Pharm. 2024;21(4):1662-1676.

[48] Rohner E, Yang R, Foo KS, et al. Unlocking the promise of mRNA therapeutics. Nat Biotechnol. 2022;40(11):1586-1600.

[49] Wang T, Li T, Niu X, et al. ADSC-derived exosomes attenuate myocardial infarction injury by promoting miR-205-mediated cardiac angiogenesis. Biol Direct. 2023;18(1):6.

[50] Lee TL, Lai TC, Lin SR, et al. Conditioned medium from adipose-derived stem cells attenuates ischemia/reperfusion-induced cardiac injury through the microRNA-221/222/PUMA/ETS-1 pathway. Theranostics (11600). 2021;11(7):3131-3149.

[51] Vadivel S, Vincent P, Sekaran S, et al. Inflammation in myocardial injury-Stem cells as potential immunomodulators for myocardial regeneration and restoration. Life Sci. 2020;250:117582.

[52] Otto Beitnes J, Oie E, Shahdadfar A, et al. Intramyocardial injections of human mesenchymal stem cells following acute myocardial infarction modulate scar formation and improve left ventricular function. Cell Transplant. 2012;21(8):1697-1709.

[53] Asahara T, Bauters C, Zheng LP, et al. Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. CIRCULATION (39918) 1995;92(9 Suppl):Ii365-371.

[54] Tomanek RJ, Sandra A, Zheng W, et al. Vascular endothelial growth factor and basic fibroblast growth factor differentially modulate early postnatal coronary angiogenesis. Circ Res. 2001;88(11):1135-1141.

[55] Kondoh K, Koyama H, Miyata T, et al. Conduction performance of collateral vessels induced by vascular endothelial growth factor or basic fibroblast growth factor. Cardiovasc Res. 2004;61(1):132-142.

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.