Function Follows Form　― A Review of Cardiac Cell Therapy ―

Abstract

The investment of nearly 2 decades of clinical investigation into cardiac cell therapy has yet to change cardiovascular practice. Recent insights into the mechanism of cardiac regeneration help explain these results and provide important context in which we can develop next-generation therapies. Non-contractile cells such as bone marrow or adult heart derivatives neither engraft long-term nor induce new muscle formation. Correspondingly, these cells offer little functional benefit to infarct patients. In contrast, preclinical data indicate that transplantation of bona fide cardiomyocytes derived from pluripotent stem cells induces direct remuscularization. This new myocardium beats synchronously with the host heart and induces substantial contractile benefits in macaque monkeys, suggesting that regeneration of contractile myocardium is required to fully recover function. Through a review of the preclinical and clinical trials of cardiac cell therapy, distinguishing the primary mechanism of benefit as either contractile or non-contractile helps appreciate the barriers to cardiac repair and establishes a rational path to optimizing therapeutic benefit.

Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

“…Therefore, taking advantage of the beneficial attributes of immaturity to preserve structural malleability and proliferative capacity while maintaining electrophysiological and/or metabolic maturity might be crucial to allow the cells to survive and engraft to their host environment post-transplantation while maximizing function and safety (Box 2). In vivo maturation of hPSC-CMs might be easier and even preferable for certain applications, such as therapeutic remuscularization after myocardial infarction, provided that engraftment-associated arrhythmias can be controlled 208 . Each PSC-CM application seems likely to require its own optimal state of cellular maturity, and, therefore, a good understanding of the various maturation strategies will be essential to achieve desirable cardiomyocyte phenotypes.…”

Is There Preclinical and Clinical Value for 19F MRI in Stem Cell Cardiac Regeneration?

“…Nevertheless, the question on whether these therapies evoke potential functional benefits is still debated. Observed variations documented by the findings of various completed and ongoing clinical trials 1 – 3 , 12 that have been/are focusing on mesenchymal SCs, cardiac progenitor cells (CPCs), embryonic stem cells (ESCs), and inducible pluripotent SCs (iPSCs) ( Table 1 ) may be attributed to (among others) the differences in the design and cell preparation parameters, suitable cell type(s), administration route(s), delivery time 13 , and end points 12 . The existing hypotheses for documented SC effects include (a) direct (cardiomyogenesis and vasculogenesis) and (b) indirect (attenuation of inflammatory responses and fibrosis, promotion of angiogenesis, and enhancement of cellular viability via paracrine/other signaling/post-translational modification mechanisms) mechanisms 12 , 14 , 15 .…”

“…Cardiovascular disease (coronary artery disease, hypertension, and heart failure) is still the primary cause of mortality and morbidity in the Western World. The basic regenerative approaches related to the use of stem cells (SCs) in cardiovascular disease have primarily targeted myocardial infarction (MI) 1 – 3 and heart failure 4 , 5 . Critical to SC interventions is a detailed understanding of the onset and progression of MI and the underlying molecular and signaling pathways.…”

The Hippo Pathway in Cardiac Regeneration and Homeostasis: New Perspectives for Cell-Free Therapy in the Injured Heart

“…Over the last two decades, considerable progress has been made in cell-based therapies, and many clinical trials have been conducted involving large cohorts of patients. Cell-based therapies are largely aimed to achieve therapeutic effects through two primary ways: the remuscularization of the injured area by exogenous healthy contractile cardiomyocytes and the activation of endogenous repair signaling through paracrine signaling [ 9 , 10 ]. However, these therapies have not led to significant improvements in cardiac function and have not succeeded in transforming contemporary cardiovascular practices [ 9 , 11 , 12 ].…”