Regenerative therapies for ischemic heart disease: From cellular strategies to organ-scale solutions

Abstract

Ischemic heart disease remains the leading cause of death worldwide, yet current therapies cannot restore lost myocardium. Heart transplantation is the only curative treatment, but it is limited by donor shortages and the risk of immune rejection. These challenges have prompted exploration of regenerative strategies designed to support repair or replacement of injured cardiac tissue. This review outlines advances across different levels of intervention. At the cellular level, stem and progenitor populations such as mesenchymal, cardiac, and induced pluripotent stem cells have been explored for their regenerative potential. Tissue engineering approaches, including scaffolds, patches, and injectable hydrogels, aim to enhance cell survival and integration. At a broader scale, organ-level strategies such as decellularization-recellularization and bioprinting represent emerging frontiers. By bringing together these complementary directions, the review highlights how progress in cardiac regeneration spans from cells to whole organs, while also emphasizing the key hurdles that continue to shape their translation.

Keywords

Ischemic heart disease / Heart failure / Myocardial regeneration / Stem cells / Tissue engineering / Bioprinting / Clinical translation

Funding

None.

Conflict of interest

Tadahisa Sugiura is an Editorial Board Member of this journal, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

References

[1] Martin SS, Aday AW, Allen NB, et al. 2025 Heart Disease and stroke statistics: A report of US and global data from the American Heart Association. Circulation. 2025; 151(8): e41-e660. doi: 10.1161/CIR.0000000000001303

[2] Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024; 45(36):3415-3537. doi: 10.1093/eurheartj/ehae177

[3] Fatehi Hassanabad A, Zarzycki AN, Fedak PWM. Cellular and molecular mechanisms driving cardiac tissue fibrosis: On the precipice of personalized and precision medicine. Cardiovasc Pathol. 2024; 71:107635. doi: 10.1016/j.carpath.2024.107635

[4] Ali SA, Mahmood Z, Mubarak Z, et al. Assessing the potential benefits of stem cell therapy in cardiac regeneration for patients with ischemic heart disease. Cureus. 2025; 17:e76770. doi: 10.7759/cureus.76770

[5] He L, Nguyen NB, Ardehali R, Zhou B. Heart regeneration by endogenous stem cells and cardiomyocyte proliferation: Controversy, fallacy, and progress. Circulation. 2020; 142(3):275-291. doi: 10.1161/CIRCULATIONAHA.119.045566

[6] Wu MY, Ali Khawaja RD, Vargas D. Heart transplantation. Radiol Clin North Am. 2023; 61(5):847-859. doi: 10.1016/j.rcl.2023.04.011

[7] Pinto AR, Ilinykh A, Ivey MJ, et al. Revisiting cardiac cellular composition. Circ Res. 2016; 118(3):400-409. doi: 10.1161/CIRCRESAHA.115.307778

[8] Tenreiro MF, Louro AF, Alves PM, Serra M. Next generation of heart regenerative therapies: Progress and promise of cardiac tissue engineering. NPJ Regen Med. 2021; 6(1):30. doi: 10.1038/s41536-021-00140-4

[9] Brickwedel J, Gulbins H, Reichenspurner H. Long-term follow-up after autologous skeletal myoblast transplantation in ischaemic heart disease. Interact Cardiovasc Thorac Surg. 2014; 18(1):61-66. doi: 10.1093/icvts/ivt434

[10] Dib N, Michler RE, Pagani FD, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: Four-year follow-up. Circulation. 2005; 112(12):1748-1755. doi: 10.1161/CIRCULATIONAHA.105.547810

[11] Arnous S, Mozid A, Martin J, Mathur A. Bone marrow mononuclear cells and acute myocardial infarction. Stem Cell Res Ther. 2012; 3(1):2. doi: 10.1186/scrt93

[12] Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circ Res. 2015; 116(8):1361-1377. doi: 10.1161/CIRCRESAHA.116.304386

[13] Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba- Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: A systematic review and meta-analysis. Circulation. 2012; 126(5):551-568. doi: 10.1161/CIRCULATIONAHA.111.086074

[14] Schächinger V, Erbs S, Elsässer A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355(12): 1210-1221. doi: 10.1056/NEJMoa060186

[15] Laflamme MA, Murry CE. Heart regeneration. Nature. 2011; 473(7347):326-335. doi: 10.1038/nature10147

[16] Guo Y, Yu Y, Hu S, Chen Y, Shen Z. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis. 2020; 11(5):349. doi: 10.1038/s41419-020-2542-9

[17] White SJ, Chong JJH. Mesenchymal stem cells in cardiac repair: Effects on myocytes, vasculature, and fibroblasts. Clin Ther. 2020; 42(10):1880-1891. doi: 10.1016/j.clinthera.2020.08.010

[18] Meng H, Cheng W, Wang L, et al. Mesenchymal stem cell exosomes in the treatment of myocardial infarction: A systematic review of preclinical in vivo studies. J Cardiovasc Transl Res. 2022; 15(2):317-339. doi: 10.1007/s12265-021-10168-y

[19] Poomani MS, Mariappan I, Perumal R, Regurajan R, Muthan K, Subramanian V. Mesenchymal stem cell (MSCs) therapy for ischemic heart disease: A promising frontier. Glob Heart. 2022; 17(1):19. doi: 10.5334/gh.1098

[20] Zhu Z, Zhu P, Fan X, Mo X, Wu X. Mesenchymal stem cell-derived exosomes: A possible therapeutic strategy for repairing heart injuries. Front Cell Dev Biol. 2023; 11:1093113. doi: 10.3389/fcell.2023.1093113

[21] Zhao L, Zhang R, Su F, et al. FoxC1-induced vascular niche improves survival and myocardial repair of mesenchymal stem cells in infarcted hearts. Oxid Med Cell Longev. 2020; 2020:1-17. doi: 10.1155/2020/7865395

[22] Madonna R, Van Laake LW, Davidson SM, et al. Position paper of the European society of cardiology working group cellular biology of the heart: Cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J. 2016; 37(23):1789-1798. doi: 10.1093/eurheartj/ehw113

[23] Han X, Liao R, Li X, et al. Mesenchymal stem cells in treating human diseases: Molecular mechanisms and clinical studies. Signal Transduct Target Ther. 2025; 10(1):262. doi: 10.1038/s41392-025-02313-9

[24] Bryl R, Kulus M, Bryja A, et al. Cardiac progenitor cell therapy: Mechanisms of action. Cell Biosci. 2024; 14(1):30. doi: 10.1186/s13578-024-01211-x

[25] Roefs MT, Bauzá-Martinez J, Van De Wakker SI, et al. Cardiac progenitor cell-derived extracellular vesicles promote angiogenesis through both associated- and co-isolated proteins. Commun Biol. 2023; 6(1):800. doi: 10.1038/s42003-023-05165-7

[26] Walravens AS, Smolgovsky S, Li L, et al. Mechanistic and therapeutic distinctions between cardiosphere-derived cell and mesenchymal stem cell extracellular vesicle non-coding RNA. Sci Rep. 2021; 11(1):8666. doi: 10.1038/s41598-021-87939-9

[27] Sugiura T, Nawaz S, Shahannaz DC, Ferrell BE, Yoshida T. From injury to repair: The therapeutic potential of induced pluripotent stem cells in heart failure. Regen Med Rep. 2025; 2(1):22-30. doi: 10.4103/REGENMED.REGENMED-D-25-00002

[28] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-676. doi: 10.1016/j.cell.2006.07.024

[29] Caudal A, Snyder MP, Wu JC. Harnessing human genetics and stem cells for precision cardiovascular medicine. Cell Genomics. 2024; 4(2):100445. doi: 10.1016/j.xgen.2023.100445

[30] Sugiura T, Nawaz S, Ferrell BE, Yoshida T. Induced pluripotent stem cells: A new dawn for the treatment of ischemic cardiomyopathy. Innov Discov. 2024; 1(4):31. doi: 10.53964/id.2024031

[31] Vo QD, Saito Y, Nakamura K, Iida T, Yuasa S. Induced pluripotent stem cell-derived cardiomyocytes therapy for ischemic heart disease in animal model: A meta-analysis. Int J Mol Sci. 2024; 25(2):987. doi: 10.3390/ijms25020987

[32] Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, et al. Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer. 2023; 22(1):189. doi: 10.1186/s12943-023-01873-0

[33] Menasché P. Cell therapy trials for heart regeneration - lessons learned and future directions. Nat Rev Cardiol. 2018; 15(11):659-671. doi: 10.1038/s41569-018-0013-0

[34] Tariq AR, Lee M, Kim M. Endothelial progenitor cells: A brief update. Int J Stem Cells. 2024; 17(4):374-380. doi: 10.15283/ijsc23106

[35] Li H, Li Z, Fu Q, Fu S, Xiang T. Exploring the landscape of exosomes in heart failure: A bibliometric analysis. Int J Surg. 2025; 111(5):3356-3372. doi: 10.1097/JS9.0000000000002248

[36] Tan F, Li X, Wang Z, Li J, Shahzad K, Zheng J. Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther. 2024; 9(1):17. doi: 10.1038/s41392-023-01704-0

[37] Saravanan JAM, Ali A, Katare R. Engineering nanoparticles and bioscaffolds for targeted microRNA delivery in cardiovascular regeneration-a comprehensive review. FASEB J. 2025; 39(14):e70871. doi: 10.1096/fj.202501226RR

[38] Li J, Sun S, Zhu D, et al. Inhalable stem cell exosomes promote heart repair after myocardial infarction. Circulation. 2024; 150(9):710-723. doi: 10.1161/CIRCULATIONAHA.123.065005

[39] Ketabat F, Alcorn J, Kelly ME, Badea I, Chen X. Cardiac tissue engineering: A journey from scaffold fabrication to in vitro characterization. Small Sci. 2024; 4:2400079. doi: 10.1002/smsc.202400079

[40] Min S, Kim S, Sim WS, et al. Versatile human cardiac tissues engineered with perfusable heart extracellular microenvironment for biomedical applications. Nat Commun. 2024; 15(1):2564. doi: 10.1038/s41467-024-46928-y

[41] Reddy MSB, Ponnamma D, Choudhary R, Sadasivuni KK. A comparative review of natural and synthetic biopolymer composite scaffolds. Polymers. 2021; 13(7):1105. doi: 10.3390/polym13071105

[42] Chen XB, Fazel Anvari-Yazdi A, Duan X, et al. Biomaterials/ bioinks and extrusion bioprinting. Bioact Mater. 2023; 28:511-536. doi: 10.1016/j.bioactmat.2023.06.006

[43] Majid QA, Fricker ATR, Gregory DA, et al. Natural biomaterials for cardiac tissue engineering: A highly biocompatible solution. Front Cardiovasc Med. 2020; 7:554597. doi: 10.3389/fcvm.2020.554597

[44] Farjaminejad S, Farjaminejad R, Hasani M, et al. Advances and challenges in polymer-based scaffolds for bone tissue engineering: A path towards personalized regenerative medicine. Polymers. 2024; 16(23):3303. doi: 10.3390/polym16233303

[45] Hudson AR, Shiwarski DJ, Kramer AJ, Feinberg AW. Enhancing viability in static and perfused 3D tissue constructs using sacrificial gelatin microparticles. ACS Biomater Sci Eng. 2025; 11(5):2888-2897. doi: 10.1021/acsbiomaterials.4c02169

[46] Liu T, Hao Y, Zhang Z, et al. Advanced cardiac patches for the treatment of myocardial infarction. Circulation. 2024; 149(25):2002-2020. doi: 10.1161/CIRCULATIONAHA.123.067097

[47] Watanabe T, Hatayama N, Guo M, Yuhara S, Shinoka T. Bridging the gap: Advances and challenges in heart regeneration from in vitro to in vivo applications. Bioengineering. 2024; 11(10):954. doi: 10.3390/bioengineering11100954

[48] Bhullar SK, Thingnam R, Kirshenbaum E, et al. Living nanofiber-enabled cardiac patches for myocardial injury. JACC Basic Transl Sci. 2025; 10(2):227-240. doi: 10.1016/j.jacbts.2024.06.010

[49] Jebran AF, Seidler T, Tiburcy M, et al. Engineered heart muscle allografts for heart repair in primates and humans. Nature. 2025; 639(8054):503-511. doi: 10.1038/s41586-024-08463-0

[50] Holme S, Richardson SM, Bella J, Pinali C. Hydrogels for cardiac tissue regeneration: Current and future developments. Int J Mol Sci. 2025; 26(5):2309. doi: 10.3390/ijms26052309

[51] Xu Q, Xiao Z, Yang Q, et al. Hydrogel-based cardiac repair and regeneration function in the treatment of myocardial infarction. Mater Today Bio. 2024; 25:100978. doi: 10.1016/j.mtbio.2024.100978

[52] Gao H, Liu S, Qin S, et al. Injectable hydrogel-based combination therapy for myocardial infarction: A systematic review and Meta-analysis of preclinical trials. BMC Cardiovasc Disord. 2024; 24(1):119. doi: 10.1186/s12872-024-03742-0

[53] Chen X, Zhong X, Huang GN. Heart regeneration from the whole-organism perspective to single-cell resolution. NPJ Regen Med. 2024; 9(1):34. doi: 10.1038/s41536-024-00378-8

[54] Bliley JM, Stang MA, Behre A, Feinberg AW. Advances in 3D bioprinted cardiac tissue using stem cell-derived cardiomyocytes. Stem Cells Transl Med. 2024; 13(5):425-435. doi: 10.1093/stcltm/szae014

[55] Tan YH, Helms HR, Nakayama KH. Decellularization strategies for regenerating cardiac and skeletal muscle tissues. Front Bioeng Biotechnol. 2022; 10:831300. doi: 10.3389/fbioe.2022.831300

[56] Kafili G, Kabir H, Jalali Kandeloos A, et al. Recent advances in soluble decellularized extracellular matrix for heart tissue engineering and organ modeling. J Biomater Appl. 2023; 38(5):577-604. doi: 10.1177/08853282231207216

[57] Liu W, Zhang X, Jiang X, Dai B, Zhang L, Zhu Y. Decellularized extracellular matrix materials for treatment of ischemic cardiomyopathy. Bioact Mater. 2024; 33:460-482. doi: 10.1016/j.bioactmat.2023.10.015

[58] Barbulescu GI, Bojin FM, Ordodi VL, Goje ID, Barbulescu AS, Paunescu V. Decellularized extracellular matrix scaffolds for cardiovascular tissue engineering: Current techniques and challenges. Int J Mol Sci. 2022; 23(21):13040. doi: 10.3390/ijms232113040

[59] Golebiowska AA, Intravaia JT, Sathe VM, Kumbar SG, Nukavarapu SP. Decellularized extracellular matrix biomaterials for regenerative therapies: Advances, challenges and clinical prospects. Bioact Mater. 2024; 32:98-123. doi: 10.1016/j.bioactmat.2023.09.017

[60] Chen TA, Zhao BB, Balbin RA, et al. Engineering a robust and anisotropic cardiac-specific extracellular matrix scaffold for cardiac patch tissue engineering. Matrix Biol Plus. 2024; 23:100151. doi: 10.1016/j.mbplus.2024.100151

[61] Bayes-Genis A, Gastelurrutia P, Monguió-Tortajada M, et al. Implantation of a double allogeneic human engineered tissue graft on damaged heart: Insights from the PERISCOPE phase I clinical trial. eBioMedicine. 2024; 102:105060. doi: 10.1016/j.ebiom.2024.105060

[62] Marino S, Alheijailan R, Alonaizan R, Gabetti S, Massai D, Pesce M. Cardiac tissue bioprinting: Integrating structure and functions through biomimetic design, bioinks, and stimulation. Gels. 2025; 11(8):593. doi: 10.3390/gels11080593

[63] Walcott JC, Davis ME. Bioprinting organoids for functional cardiac constructs: Progress and unmet challenges. Int J Bioprinting. 2025; 11(3):85-114. doi: 10.36922/IJB025150134

[64] Akter MZ, Tufail F, Ahmad A, et al. Harnessing native blueprints for designing bioinks to bioprint functional cardiac tissue. iScience. 2025; 28(3):111882. doi: 10.1016/j.isci.2025.111882

[65] Finkel S, Sweet S, Locke T, et al. FRESH^TM3D bioprinted cardiac tissue, a bioengineered platform for in vitro pharmacology. APL Bioeng. 2023; 7(4):046113. doi: 10.1063/5.0163363

[66] Kim M, Hwang DG, Jang J. Bioprinting approaches in cardiac tissue engineering to reproduce blood-pumping heart function. iScience. 2025; 28(1):111664. doi: 10.1016/j.isci.2024.111664

[67] Kim SJ, Jang J. Advances in 3D bioprinting technologies for cardiovascular intervention and regeneration therapeutics. J Cardiovasc Interv. 2025; 4(1):1. doi: 10.54912/jci.2024.0027

[68] Ershad F, Rao Z, Maharajan S, et al. Bioprinted optoelectronically active cardiac tissues. Sci Adv. 2025; 11(4):eadt7210. doi: 10.1126/sciadv.adt7210

[69] Bois A, Grandela C, Gallant J, Mummery C, Menasché P. Revitalizing the heart: Strategies and tools for cardiomyocyte regeneration post-myocardial infarction. NPJ Regen Med. 2025; 10(1):6. doi: 10.1038/s41536-025-00394-2

[70] Movahed AY, Bagheri R, Savatier P, Šarić T, Moradi S. Elimination of tumorigenic pluripotent stem cells from their differentiated cell therapy products: An important step toward ensuring safe cell therapy. Stem Cell Rep. 2025; 20(7):102543. doi: 10.1016/j.stemcr.2025.102543

[71] Deuse T, Schrepfer S. Progress and challenges in developing allogeneic cell therapies. Cell Stem Cell. 2025; 32(4):513-528. doi: 10.1016/j.stem.2025.03.004

[72] Khera R, Oikonomou EK, Nadkarni GN, et al. Transforming cardiovascular care with artificial intelligence: From discovery to practice. J Am Coll Cardiol. 2024; 84(1):97-114. doi: 10.1016/j.jacc.2024.05.003

[73] Garmany A, Terzic A. Artificial intelligence powers regenerative medicine into predictive realm. Regen Med. 2024; 19(12):611-616. doi: 10.1080/17460751.2024.2437281

[74] Griffith BP, Goerlich CE, Singh AK, et al. Genetically modified porcine-to-human cardiac xenotransplantation. N Engl J Med. 2022; 387(1):35-44. doi: 10.1056/NEJMoa2201422

[75] Moazami N, Stern JM, Khalil K, et al. Pig-to-human heart xenotransplantation in two recently deceased human recipients. Nat Med. 2023; 29(8):1989-1997. doi: 10.1038/s41591-023-02471-9

[76] Phillips KG, Aljabban I, Wolbrom DH, et al. Cardiac xenotransplantation: Current state and future directions. Circulation. 2025; 152(1):58-73. doi: 10.1161/CIRCULATIONAHA.124.070875