Reviewing Efforts to Use Cells and Scaffolds to Regenerate the Heart

The heart is one of the least regenerative tissues in the body. Damage resulting from loss of blood flow during a heart attack leads to scarring and loss of function, rather than any meaningful degree of regeneration. While preventing the atherosclerosis that causes occlusion of blood vessels is the most desirable goal, finding ways to repair a damaged heart is also a high priority for the research community. Many groups have worked towards regenerative therapies based on delivery of cells and scaffolding material, even layers of artificial tissue made by combining the two, but progress has been frustratingly slow.

Cardiovascular diseases (CVD) are the leading cause of hospitalization and death globally. CVD includes disturbances of the heart rhythm, cardiac valve pathologies, genetically driven malformations and, ultimately, peripheral artery disease (PAD) or coronary artery disease (CAD), which may culminate, respectively, in critical limb ischemia (CLI) and heart failure (HF). The use of cells with stem/progenitor characteristics in PAD and CLI has shown a success in clinical translation to a certain extent, given the ability of the chosen cells (e.g., derived from bone marrow, peripheral blood, or cord blood) to promote de novo vasculogenesis by a robust "paracrine effect". By contrast, the use of a similar setting to regenerate the contractile mass of the heart to compensate the loss of myocytes due to acute/chronic ischemia and/or inflammation has been largely unsuccessful and controversial, due to the absence of resident stem cells that could be activated in situ and/or expanded in vitro prior to being reinjected into the failing hearts.

Alternatives to this deficiency have been sought in the use of induced pluripotent stem cells (iPSCs), whose derived cardiomyocytes (CMs) have been employed in preclinical models in small and large animals, and even in pioneering studies in humans. Although scaled-up systems to produce therapeutic quantities of these cells with enhanced purity have been set, anticipating industrial production, several caveats have been expressed due to risks of arrhythmogenicity, incomplete maturation, potential tumor formation, and (at least for allogenic use) immune reactions.

Given the lack of endogenous regenerative capacity of the myocardium, the consequence of acute/chronic cardiac ischemia is still considered an irreparable damage leading to progressive replacement of the contractile cells with a stiff, fibrotic scar. Under these conditions, the heart undergoes a series of morphological transformations (e.g., rearrangement of the contractile apparatus and modification of the geometry), changes in mechanical characteristics and reduction of the pumping efficiency, representing signs of HF. With the advent of tissue engineering, the introduction of biological fabrication methods combined with refined systems for cellular genetic manipulation and decryption of mechanosensitive cues has enabled new strategies to enhance the efficacy of cardiac cell therapy and the elaboration of disease modeling systems using scaffolds, tissue printing, and tissue engineering approaches. This renews the hope that after the disappointment arising from the failure of the "classical" cell therapy approaches, it will be possible to reach a condition to regenerate the human heart, which still represents the "holy grail" of cardiology.