To Repair a Broken Heart: Stem Cells in Ischemic Heart Disease

Abstract

Despite improvements in contemporary medical and surgical therapies, cardiovascular disease (CVD) remains a significant cause of worldwide morbidity and mortality; more specifically, ischemic heart disease (IHD) may affect individuals as young as 20 years old. Typically managed with guideline-directed medical therapy, interventional or surgical methods, the incurred cardiomyocyte loss is not always completely reversible; however, recent research into various stem cell (SC) populations has highlighted their potential for the treatment and perhaps regeneration of injured cardiac tissue, either directly through cellular replacement or indirectly through local paracrine effects. Different stem cell (SC) types have been employed in studies of infarcted myocardium, both in animal models of myocardial infarction (MI) as well as in clinical studies of MI patients, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), Muse cells, multipotent stem cells such as bone marrow-derived cells, mesenchymal stem cells (MSCs) and cardiac stem and progenitor cells (CSC/CPCs). These have been delivered as is, in the form of cell therapies, or have been used to generate tissue-engineered (TE) constructs with variable results. In this text, we sought to perform a narrative review of experimental and clinical studies employing various stem cells (SC) for the treatment of infarcted myocardium within the last two decades, with an emphasis on therapies administered through thoracic incision or through percutaneous coronary interventions (PCI), to elucidate possible mechanisms of action and therapeutic effects of such cell therapies when employed in a surgical or interventional manner.

Keywords: cardiac regeneration; cardiac surgery; cardiomyocyte proliferation; cardiovascular disease; cell sheets; coronary artery disease; multipotent stem cells; myocardial infarction; myocardial patch; pluripotent stem cells; tissue engineering.

Figure 1

Stem and progenitor cell therapies for ischemic heart disease—pluripotent stem cell therapies (created with BioRender.com, accessed on 24 February 2024) [89,90,91]. CM, Cardiomyocyte; TIMP-1, tissue inhibitor of metalloproteinase 1; LV, left ventricle; BF, blood flow; VTach, ventricular tachycardia; VWall, ventricular wall; LVEF, left ventricular ejection fraction; iPSC, induced pluripotent stem cells; hPSC, human pluripotent stem cells; MSC, mesenchymal stem cells; ESCs, embryonic stem cells; CHF, congestive heart failure; CABG, coronary artery bypass graft; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention.

Figure 2

Stem and progenitor cell therapies for ischemic heart disease—multipotent stem cell therapies (created with BioRender.com, accessed on 24 February 2024) [115,116,117,118,122,123,126,127,128]. LV, left ventricle; LVESV, left ventricular end systolic volume; LVEF, left ventricular ejection fraction; MSC, mesenchymal stem cells; CABG, coronary artery bypass graft; STEMI, ST-elevation myocardial infarction; BM, bone marrow; BMC, bone marrow cells; BMSCs, bone marrow stem cells; BM-MNC, bone marrow mononuclear cells; MNC, mononuclear cells; c-KIT, tyrosine protein kinase kit; C-CURE, cardiopoietic stem cell therapy in heart failure; TIME, timing in myocardial infarction evaluation; PCI, percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; Akt, protein kinase B; Igf-1; Insulin-like growth factor 1; VEGF, vascular endothelial growth factor; SDF-1, stromal cell-derived factor 1; TGF-β, transforming growth factor beta; ADRC, adipose-derived regenerative cells; UC-MSC, umbilical cord mesenchymal stem cells; CSC, cardiac stem cell; CPC, cardiac progenitor cell; SCIPIO, stem cell infusion in patients with ischemic cardiomyopathy; CADUCEUS, cardiosphere-derived autologous stem cells to reverse ventricular dysfunction; SC, stem cell.

Figure 3

Tissue engineering (TE) therapies for ischemic heart disease—Pluripotent TE constructs (created with BioRender.com, accessed on 24 February 2024). TE, tissue engineering; ESC, embryonic stem cells; iPSC, induced pluripotent stem cells; PSC, pluripotent stem cells; CTS, cardiac tissue sheet; L-CTS, large cardiac tissue sheet; CM, cardiomyocyte; LAD, left anterior descending coronary artery; hCMP, human cardiac muscle patch; hPSC, human pluripotent stem cell; hESC, human embryonic stem cell; SMC, smooth muscle cells; AEC, arterial endothelial cells; CF, cardiac fibroblast.

Figure 4

Tissue engineering (TE) therapies for ischemic heart disease—Multipotent TE constructs (created with BioRender.com, accessed on 24 February 2024). TE, tissue engineering; CM, cardiomyocyte; LAD, left anterior descending coronary artery; MSC, mesenchymal stem cells; hCSC, human cardiac stem cells; hMSC, human mesenchymal stem cells; AD-MSC, adipose-derived mesenchymal stem cells; GAG, glycosaminoglycans; PLCL, poly(lactide-co-ε-caprolactone); P(NIPAM-AA), poly(N-isopropylacrylamine-co-acrylic acid); VEGF, vascular endothelial growth factor; IGF-1, insulin-like growth factor 1; SDF-1, stromal cell-derived factor-1.