Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions

Abstract

Despite significant therapeutic advances, the prognosis of patients with heart failure (HF) remains poor, and current therapeutic approaches are palliative in the sense that they do not address the underlying problem of the loss of cardiac tissue. Stem cell-based therapies have the potential to fundamentally transform the treatment of HF by achieving what would have been unthinkable only a few years ago-myocardial regeneration. For the first time since cardiac transplantation, a therapy is being developed to eliminate the underlying cause of HF, not just to achieve damage control. Since the initial report of cell therapy (skeletal myoblasts) in HF in 1998, research has proceeded at lightning speed, and numerous preclinical and clinical studies have been performed that support the ability of various stem cell populations to improve cardiac function and reduce infarct size in both ischemic and nonischemic cardiomyopathy. Nevertheless, we are still at the dawn of this therapeutic revolution. Many important issues (eg, mechanism(s) of action of stem cells, long-term engraftment, optimal cell type(s), and dose, route, and frequency of cell administration) remain to be resolved, and no cell therapy has been conclusively shown to be effective. The purpose of this article is to critically review the large body of work performed with respect to the use of stem/progenitor cells in HF, both at the experimental and clinical levels, and to discuss current controversies, unresolved issues, challenges, and future directions. The review focuses specifically on chronic HF; other settings (eg, acute myocardial infarction, refractory angina) are not discussed.

Keywords: heart failure; myocardial infarction; myocardial regeneration; stem cells.

Figure 1. Use of various types of stem cell therapies in patients with cardiovascular disease

Illustrated is the number of patients treated with six major types of cells from 2000 (when the first cell therapy for heart disease was performed) to 2012.

Figure 2. Sources of stem cells used for cardiac repair

Bone marrow-derived stem cells include a broad range of cells, from mesenchymal stem cells to endothelial progenitor cells, hematopoietic stem cells, and unfractionated mononuclear cells. (Illustration Credit: Ben Smith)

Figure 3. Potential mechanisms of action of stem cells

Implantation of stem cells in the injured heart initiates myocardial repair via several direct and indirect mechanisms: activation of endogenous precursors, differentiation into cardiac and vascular cells, promotion of neovascularization, favorable modulation of the extracellular matrix, and inhibition of apoptosis. Together these events reduce adverse cardiac remodeling and hypertrophy, increase perfusion, and improve cardiac function, leading to improvement in clinical status. (Illustration Credit: Ben Smith)