Unchain my heart: the scientific foundations of cardiac repair

Abstract

In humans, the biological limitations to cardiac regenerative growth create both a clinical imperative--to offset cell death in acute ischemic injury and chronic heart failure--and a clinical opportunity; that is, for using cells, genes, and proteins to rescue cardiac muscle cell number or in other ways promote more efficacious cardiac repair. Recent experimental studies and early-phase clinical trials lend credence to the visionary goal of enhancing cardiac repair as an achievable therapeutic target.

Figure 1

Sources of cells for cardiac repair, and routes of their administration. (A) Cells in current human trials include skeletal muscle myoblasts, unfractionated bone marrow, and circulating (endothelial) progenitor cells. Cells in preclinical studies include bone marrow MSCs, multipotent cells from other sources, and novel progenitor or stem cells discovered in the adult myocardium; see text for details. (B) Existing trials use intracoronary delivery routes (over-the-wire balloon catheters), intramuscular delivery via catheters (e.g., the NOGA system for electromechanical mapping), or direct injection during cardiac surgery. Not represented here are the theoretical potential for systemic delivery, suggested by the homing of some cell types to infarcted myocardium (39), and strategies to mobilize endogenous cells from other tissue sites to the heart.

Figure 2

Mechanisms of action. Progenitor cells may improve functional recovery of infarcted or failing myocardium by various potential mechanisms, including direct or indirect improvement of neovascularization. Paracrine factors released by progenitor cells may inhibit cardiac apoptosis, affect remodeling, or enhance endogenous repair (e.g., by tissue-resident progenitor cells). Differentiation into cardiomyocytes may contribute to cardiac regeneration. The extent to which these different mechanisms are active may critically depend on the cell type and setting, such as acute or chronic injury.

Figure 3

Mobilization and homing. After intravascular delivery or mobilization from bone marrow, progenitor cells are targeted to the sites of injury by multiple signals. Homing is mediated by a multistep process including the initial adhesion, transmigration, and invasion. Molecular mechanisms contributing to these individual steps are indicated but likely vary depending on the cell type and model. EPO, erythropoietin; MCP-1, monocyte chemoattractant protein–1.

Figure 4

Current challenges for cell-based therapy in cardiac repair include identifying the origins of the novel cardiac progenitor and stem cells found within the heart, pinpointing the biologically active cells from bone marrow and other mixed populations, optimizing cell mobilization and homing, augmenting grafted cells’ survival, defining the cues for cardiac differentiation, promoting donor cell proliferation ex vivo (or, if safe, in vivo), and exploiting cell therapy as a platform for secretory signals.