Commentary: Neonatal applications of cardiac cell therapy: It’s good to be young!

The decades-long march to harness the regenerative properties of stem cells for the purposes of myocardial regeneration has been frustrating, with recent meta-analyses and expert consensus reports questioning the efficacy of these efforts and the validity of purported underlying mechanisms of action.^1,2 Sano and colleagues³ summarize these and other recent reports and propose that the answer to this challenge may be found by turning to youth. Specifically, cardiac progenitor cells and cardiosphere-derived cells harvested from neonatal hearts may offer greater regenerative therapeutic benefit compared with use of adult cells. This potency is ascribed to a higher prevalence of these cells in juvenile heart tissue, their improved proliferative and differentiation potential, and their increased secretion of paracrine mediators with regenerative properties.

One intriguing implication of this observation is that neonatal patients with congenital heart disease may derive greater benefit from cell therapy compared with adult patients. Patients with complex congenital heart disease typically undergo multiple operations in a relatively short period, providing an ideal opportunity for harvesting and administering autogenous pluripotent cells. More importantly, cell therapy can be administered to these individuals before myocardial damage occurs and thereby delay or prevent the development of heart failure, a near-universal outcome after the performance of palliative procedures for congenital heart disease.⁴ Although heart failure in this population is multifactorial, a key underlying mechanism is insufficient adaption of myocardium to combined pressure and volume overload, leading to progressive cardiac dilation, fibrosis, and contractile failure.⁵ Cell therapy at the time of palliation may reduce this damage by promoting physiological adaption. This preventive therapeutic role contrasts starkly with cell therapy applications in adult ischemic heart disease, where cellular implantation has typically been applied as a rescue rather than preventative therapy.

Although findings for cardiac cell therapy in the pediatric population are encouraging, it would be imprudent to ignore hard-won lessons from the past 2 decades of preclinical and clinical investigations in adult patients. Short-term improvements in surrogate outcome measures in early, under-powered trials were embraced with unrealistic exuberance in these adult studies. The resulting enthusiasm prompted a flood of subsequent trials despite a limited understanding of critical potential success factors, including definition of an optimal target patient population, cell type, dosing, route of administration, or even a strong base of knowledge of underlying mechanisms of action. This lack of understanding allowed for inappropriate application of cell implantation, including, in retrospect, its illogical administration to large areas of ischemic chronic infarction with the goal of generating functional muscle.^6,7

Whereas extensive basic and translational research is ongoing to fill persistent knowledge gaps in the utility of cell therapy, only a small portion of this work is directed toward examination of its use in congenital heart disease. This is particularly true for analysis of the effects of progenitor cell administration to young patients with systemic right ventricle pathology or pronounced abnormalities in structure, cellular composition, and functional responses to hemodynamic perturbations.^5,8

To avoid the mistakes of premature cell therapy trials in adult patients, proponents of pediatric cell therapy should ideally perform rigorous optimization of cell therapy in preclinical models of congenital heart disease. The resulting base of knowledge will provide the best opportunity for success in future clinical trials, preferably with adequately sized study populations and appropriate randomized, blinded trial design.

CENTRAL MESSAGE.

Neonatal hearts possess progenitor cell populations that may have regenerative properties greater than that demonstrated by corresponding adult cell populations.

Biography

Christopher T. Ryan, MD, and Todd K. Rosengart, MD