Maximizing Cardiac Repair: Should We Focus on the Cells or on the Matrix?

Abstract

A major characteristic of stem cells is their ability to respond to their environment and differentiate accordingly; yet, in the context of cardiac repair, where stem or progenitor cells are delivered into injured myocardium, the local cell environment is often ignored. Damaged myocardium lacks the 3-dimensional complexity, fiber orientation, vascularity, and biochemistry of native heart. When cell therapy shows reparative effects, the changes are often seen at the scar border, where matrix thickness, stiffness, and fiber orientation are more nearly normal. Augmenting the mechanical, biochemical, and vascular milieu of damaged myocardium through tissue engineering could both increase cell delivery and potentially restore native cues for cell behavior to enhance the effectiveness of cell-based cardiac repair. An accepted dogma regarding stem cells is their capacity to differentiate in response to environmental cues. Cardiovascular cell–based therapy is founded on the assumptions that stem/progenitor cells are present in adult tissues; that cells can be harvested and delivered (or mobilized) to an injury site; and that once they are present, cells can promote repair. Yet, in dozens of clinical studies examining a variety of clinical outcomes, conducted with different cell types, delivery methods, and times after injury, the functional benefits of cardiac cell therapy have been minimal. In ischemic heart disease, the observed functional effects are usually localized to the infarct border zone,1 and because the cells themselves do not persist, the effects are attributed to paracrine factors. For the sake of this article, tissue engineering is defined as the use of a structural material (eg, scaffold)—used alone or in combination with molecules, microRNAs, genes, or cells—to improve or replace the biological function of injured cardiac tissue. We consider the question, “Could engineered tissue that recapitulates the characteristics of native healthy myocardium provide a cell delivery or recruitment system that increases cell retention, …