Healing the Ischaemic Heart: A Critical Review of Stem Cell Therapies

Abstract

Ischaemic heart disease (IHD) remains the leading cause of mortality worldwide. Current pharmaceutical treatments focus on delaying, rather than preventing disease progression. The only curative treatment available is orthotopic heart transplantation, which is greatly limited by a lack of available donors and the possibility for immune rejection. As a result, novel therapies are consistently being sought to improve the quality and duration of life of those suffering from IHD. Stem cell therapies have garnered attention globally owing to their potential to replace lost cardiac cells, regenerate the ischaemic myocardium and to release protective paracrine factors. Despite recent advances in regenerative cardiology, one of the biggest challenges in the clinical translation of cell-based therapies is determining the most efficacious cell type for repair. Multiple cell types have been investigated in clinical trials; with inconsistent methodologies and isolation protocols making it difficult to draw strong conclusions. This review provides an overview of IHD focusing on pathogenesis and complications, followed by a summary of different stem cells which have been trialled for use in the treatment of IHD, and ends by exploring the known mechanisms by which stem cells mediate their beneficial effects on ischaemic myocardium.

Keywords: adult stem cells; clinical trials; ischaemic heart disease; paracrine mechanisms; pluripotent stem cells; stem cells.

Fig. 1.

Pathogenesis and Complications of IHD. Figure summarising the development and progression of the atherosclerotic plaque, which obstructs the coronary lumen and if unstable—can rupture, with subsueqent thrombus formation occluding the affected coronary artery—resulting in acute coronary syndromes. LDL, low density lipoprotein; VCAM1, vascular cell adhesion molecule 1; CCL2, chemoattractant protein 1; ROS, reactive oxygen species; LDLox, oxidised LDL; IFN-Y, interferon gamma; TNF-$\alpha$, tumour necrosis factor alpha; IL-2, interleukin 2; IL-3, interleukin 3; IL-10, interleukin 10; TGF$\beta$, transforming growth factor beta; Th1, T helper type 1; $T_{\text{reg}}$, regulatory T cell.

Fig. 2.

The Cycle of Heart Failure. In response to myocardial injury, neurohumoral mechanisms are activated, compensating for decreased cardiac output. However, in the long term, these mechanisms cause further wall stress and cardiac remodelling, further damaging cardiac tissue and advancing the progression of heart failure. RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

Fig. 3.

Sources of Stem Cells Used in Cardiac Repair. Figure summarising the most significant sources of stem cells used for cardiac repair. Pluripotent stem cells can be obtained from the inner cell mass or generated from somatic cells by introducing specific transcription factors. Adult stem cells exhibit multipotency and are derived from various adult tissues and organs.

Fig. 4.

Stem Cell Mechanisms for Cardiac Repair. Summary of the proposed mechanisms for cardiac repair by transplanted stem cells. Stem cells secrete various factors with a paracrine effect on other cells promoting cardioprotection, neovascularisation, immunomodulation and endogenous stem cell activation, along with an autocrine feedback effect to enhance their survival. IL-10, interleukin 10; IL-1$\beta$, interleukin one beta; IL-6, interleukin 6; TNF-$\alpha$, tumour necrosis factor alpha; MCP-1, monocyte chemoattractant protein 1; IL-12, interleukin 12; PGE2, prostaglandin E2; RISK, reperfusion injury salvage kinase; SAFE, surviving factor enhancement; PKC$\epsilon$, protein kinase C epsilon; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-related kinase; JAK, janus tyrosine kinase; STAT, signal transducer and activator of transcription; IGF-1, insulin-like growth factor-1; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; EGF, epidermal growth factor; IL-11, interleukin-11; bFGF; basic fibroblast growth factor; EPO, erythropoietin; RAS, rat sarcoma virus protein; STAT3, signal transducer and activator of transcription 3; Ang-1, angiopoietin-1; Tie2, tyrosine kinase with immunoglobulin-like loops and epidermal growth factor homology domains-2; SCF, stem cell factor; CPC, cardiac progenitor cell; SDF-1$\alpha$, stromal cell-derived factor 1-alpha; EPC, endothelial progenitor cell; HSC, haemopoietic stem cell; ECFC, endothelial colony-forming cell.