Cardiac regenerative capacity is age- and disease-dependent in childhood heart disease

Abstract

ObjectiveWe sought to define the intrinsic stem cell capacity in pediatric heart lesions, and the effects of diagnosis and of age, in order to inform evidence-based use of potential autologous stem cell sources for regenerative medicine therapy.MethodsVentricular explants derived from patients with hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TF), dilated cardiomyopathy (DCM) and ventricular septal defect (VSD) were analyzed following standard in vitro culture conditions, which yielded cardiospheres (C-spheres), indicative of endogenous stem cell capacity. C-sphere counts generated per 5 mm3 tissue explant and the presence of cardiac progenitor cells were correlated to patient age, diagnosis and echocardiographic function.ResultsCardiac explants from patients less than one year of age with TF and DCM robustly generated c-kit- and/or vimentin-positive cardiac mesenchymal cells (CMCs), populating spontaneously forming C-spheres. Beyond one year of age, there was a marked reduction or absence of cardiac explant-derivable cardiac stem cell content in patients with TF, VSD and DCM. Stem cell content in HLHS and DCM strongly correlated to the echocardiographic function in the corresponding ventricular chamber, with better echocardiographic function correlating to a more robust regenerative cellular content.ConclusionsWe conclude that autologous cardiomyogenic potential in pediatric heart lesions is robust during the first year of life and uniformly declines thereafter. Depletion of stem cell content occurs at an earlier age in HLHS with the onset of ventricular failure in a chamber-specific pattern that correlates directly to ventricular dysfunction. These data suggest that regenerative therapies using autologous cellular sources should be implemented in the neonatal period before the potentially rapid onset of single ventricle failure in HLHS or the evolution of biventricular failure in DCM.

Update on stem cell technologies in congenital heart disease

“…Within these disease subgroups, results based on the age of patient were studied as well. 12 Results showed an extensive loss of production of C-spheres in ventricular tissue from patients beyond 1 year of age, a finding that appeared to be consistent across multiple heart disease disorders evaluated in this study. With regard to tissue from patients with HLHS, C-sphere production declined in samples from patients who had evidence of ventricular failure despite being less than 1 year of age.…”

“…While the use of cardiac stem cells has been more extensively evaluated in adult ischemic heart disease, evidence suggests that the regenerative ability of cardiac tissue including cardiac progenitor cell (CPC) content may decline with age. [11][12][13] Therefore, there has been more recent interest in assessing the therapeutic potential of CPCs in the pediatric setting. A recent study evaluated the regenerative capabilities of cardiac mesenchymal cells (CMCs) with regard to the age of the patient and type of heart disease.…”

Heart failure therapy based on interventricular mechanics and cardio-vascular communications

“…In summary, there are enormous endogenous potentials for functional recovering a diseased heart in particular in infancy. In addition, heart failure has not only age but also disease related specifics (46). In contrast to heart failure of a right ventricle in sub-aortic position (HLHS), DCM is characterized by quite higher regenerative properties (46).…”

“…In addition, heart failure has not only age but also disease related specifics (46). In contrast to heart failure of a right ventricle in sub-aortic position (HLHS), DCM is characterized by quite higher regenerative properties (46). However, despite a dramatic gain in knowledge, it seems to be still a long way to have an exogenous cocktail available to achieve reparation and cardiac regeneration.…”

Cardiac differentiation of bone marrow resident c-kit+ stem cells by L-carnitine increases through secretion of VEGF, IL6, IGF-1 and TGF-β

“…Hence, finding suitable method/methods to recover cardiac cells after AMI is the final purpose at the heart research centers [5]. Recently, stem cells usage has been known as an attractive method, which could regenerate and repair the lost heart organ [6]. Nowadays, broadly used cells in the animal modeling are modeling that are somatic stem cells from various adult tissues, embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells [7,8].…”