Human Neonatal Cardiovascular Progenitors: Unlocking the Secret to Regenerative Ability

Abstract

Although clinical benefit can be achieved after cardiac transplantation of adult c-kit+ or cardiosphere-derived cells for myocardial repair, these stem cells lack the regenerative capacity unique to neonatal cardiovascular stem cells. Unraveling the molecular basis for this age-related discrepancy in function could potentially transform cardiovascular stem cell transplantation. In this report, clonal populations of human neonatal and adult cardiovascular progenitor cells were isolated and characterized, revealing the existence of a novel subpopulation of endogenous cardiovascular stem cells that persist throughout life and co-express both c-kit and isl1. Epigenetic profiling identified 41 microRNAs whose expression was significantly altered with age in phenotypically-matched clones. These differences were correlated with reduced proliferation and a limited capacity to invade in response to growth factor stimulation, despite high levels of growth factor receptor on progenitors isolated from adults. Further understanding of these differences may provide novel therapeutic targets to enhance cardiovascular regenerative capacity.

Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells

“…miRNA are well described post-transcriptional regulators of gene expression, participating in many pathophysiological mechanisms in the cardiovascular system56, as well as in progenitors biology and cardiomyocyte proliferation5758. Additionally, miRNA expression can be affected by β-blockers treatment, and miRNAs can be directly involved in the β-adrenergic transduction cascade578.…”

Simulated Microgravity Exerts an Age-Dependent Effect on the Differentiation of Cardiovascular Progenitors Isolated from the Human Heart

“…With age, the regenerative capacity of cardiovascular progenitors found within the heart decreases [ 12 ]. We have previously reported that Isl-1 positive cardiovascular progenitors isolated from the neonatal and adult heart exhibit age—dependent disparities in functional parameters such as cell cycle progression and invasion which may stem from underlying differences in gene and microRNA expression [ 13 ]. Determining the effect of simulated microgravity on resident cardiac progenitor cell function in vitro , and whether this effect is dependent on age would have implications not only for space flight, but would also provide evidence as to whether alterations in gravitational force could be utilized as a therapeutic for improved cardiovascular stem cell function.…”

Multipotent stem cells of the heart—do they have therapeutic promise?

“…Murine or human Isl1 + cells derived from embryonic stem cells have been shown to give rise to cardiomyocytes, which exhibit appropriate electrophysiological properties, such as action potentials and Ca 2+ transients (Cagavi et al, 2014 ), as well as smooth muscle cells and endothelial cells (Lui et al, 2013 ). Contrary to previous assumptions, Isl1 + cells are not exclusively in an embryonic state because there is a subpopulation of endogenous CSCs that persist throughout life and co-express both c-kit and isl1 (Fuentes et al, 2013 ). Because all progenitor cells expressing Isl1 also express c-kit but not all c-kit + cells express Isl1, Isl1 + c-kit + progenitor cells may be a subpopulation of c-kit + progenitors (Fuentes et al, 2013 ).…”

“…Contrary to previous assumptions, Isl1 + cells are not exclusively in an embryonic state because there is a subpopulation of endogenous CSCs that persist throughout life and co-express both c-kit and isl1 (Fuentes et al, 2013 ). Because all progenitor cells expressing Isl1 also express c-kit but not all c-kit + cells express Isl1, Isl1 + c-kit + progenitor cells may be a subpopulation of c-kit + progenitors (Fuentes et al, 2013 ).…”

“…Comparisons of embryonic and adult Isl1 + cells have revealed that their significantly different levels of proliferative and migratory abilities are a consequence of age (Fuentes et al, 2013 ). Cardiac progenitor cells derived from embryonic stem cells may be a valid source for cell-based cardiac-repair therapies because their use would address the age-related decline in cardiac progenitor cell function; furthermore, the potential risk of teratoma formation and genomic alterations attributed to embryonic cells is minimal for Isl1 + cells because they are highly committed cardiovascular cells (Cagavi et al, 2014 ).…”