Dynamics of Human Myocardial Progenitor Cell Populations in the Neonatal Period

Stanford University, Palo Alto, California, United States
The Annals of thoracic surgery (Impact Factor: 3.85). 11/2008; 86(4):1311-9. DOI: 10.1016/j.athoracsur.2008.06.058
Source: PubMed


Pluripotent cardiac progenitor cells resident in myocardium offer a potentially promising role in promoting recovery from injury. In pediatric congenital heart disease (CHD) patients, manipulation of resident progenitor cells may provide important new approaches to improving outcomes. Our study goals were to identify and quantitate populations of progenitor cells in human neonatal myocardium during the early postnatal period and determine the proliferative capacity of differentiated cardiac myocytes.
Immunologic markers of cell lineage (stage-specific embryonic antigen 4 [SSEA-4], islet cell antigen 1 [Isl1], c-kit, Nkx2.5, sarcoplasmic reticulum calcium-regulated ATPase type 2 [SERCA2]) and proliferation (Ki67) were localized in right ventricular biopsies from 32 CHD patients aged 2 to 93 days.
Neonatal myocardium contains progenitor cells and transitional cells expressing progenitor and differentiated myocyte marker proteins. Some cells expressed the pluripotent cell marker c-kit and also coexpressed the myocyte marker SERCA2. Multipotent progenitor cells, identified by the expression of Isl1, were found. Ki67 was expressed in some myocytes and in nonmyocyte cells. A few cells expressing SSEA-4 and Isl1 were observed during the early postnatal period. Cells expressing c-kit, the premyocyte marker Nkx2.5, and Ki67 were found throughout the first postnatal month. A progressive decline in cell density during the first postnatal month was observed for c-kit+ cells (p = 0.0013) and Nkx2.5+ cells (p = 0.0001). The percentage of cells expressing Ki67 declined during the first 3 postnatal months (p = 0.0030).
Cells in an incomplete state of cardiomyocyte differentiation continue to reside in the infant heart. However, the relative density of progenitor cells declines during the first postnatal month.

Download full-text


Available from: Robert Kirk Riemer, Oct 06, 2014
  • Source
    • "Histological analysis suggests that cells positive for Isl1, and SSEA-4 (an early stem cell marker) are abundant in the fetus and are only sporadically found in the neonate. Cells expressing c-kit and Nkx2.5 decline in number significantly as a neonate transitions into an infant [8], [9]. A gradual reduction of proliferation occurs in the heart at this time; during the neonatal period there are 3 times as many proliferating cells as those identified in children >2 years of age [9]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Oct 2013 · PLoS ONE
  • Source
    • "During this disease process, cardiac progenitor cells have been reported to migrate to the injury site, differentiate into cardiomyocytes, and eventually, regenerate the myocardium [7]–[8]. However, the native population of cardiac progenitor cells is extremely limited and decreases significantly during the aging process, compromising its repair potential [9]. In order to replace the lost cardiomyocytes and regenerate the myocardium, cell transplantation is emerging as a potentially useful therapeutic strategy to restore cardiac function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apelin is a peptide ligand for an orphan G-protein coupled receptor (APJ receptor) and serves as a critical gradient for migration of mesodermal cells fated to contribute to the myocardial lineage. The present study was designed to establish a robust cardiac differentiation protocol, specifically, to evaluate the effect of apelin on directed differentiation of mouse and human embryonic stem cells (mESCs and hESCs) into cardiac lineage. Different concentrations of apelin (50, 100, 500 nM) were evaluated to determine its differentiation potential. The optimized dose of apelin was then combined with mesodermal differentiation factors, including BMP-4, activin-A, and bFGF, in a developmentally specific temporal sequence to examine the synergistic effects on cardiac differentiation. Cellular, molecular, and physiologic characteristics of the apelin-induced contractile embryoid bodies (EBs) were analyzed. It was found that 100 nM apelin resulted in highest percentage of contractile EB for mESCs while 500 nM had the highest effects on hESCs. Functionally, the contractile frequency of mESCs-derived EBs (mEBs) responded appropriately to increasing concentration of isoprenaline and diltiazem. Positive phenotype of cardiac specific markers was confirmed in the apelin-treated groups. The protocol, consisting of apelin and mesodermal differentiation factors, induced contractility in significantly higher percentage of hESC-derived EBs (hEBs), up-regulated cardiac-specific genes and cell surface markers, and increased the contractile force. In conclusion, we have demonstrated that the treatment of apelin enhanced cardiac differentiation of mouse and human ESCs and exhibited synergistic effects with mesodermal differentiation factors.
    Full-text · Article · Jun 2012 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Microgravity has a profound effect on cardiovascular function, however, little is known about the impact of microgravity on progenitors that reside within the heart. We investigated the effect of simulated microgravity exposure on progenitors isolated from the neonatal and adult human heart by quantifying changes in functional parameters, gene expression and protein levels after 6-7 days of 2D clinorotation. Utilization of neonatal and adult cardiovascular progenitors in ground-based studies has provided novel insight into how microgravity may affect cells differently depending on age.
    Full-text · Article · Jul 2015 · PLoS ONE
Show more