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Original Articles: Pediatric Cardiac

Invited Commentary

Division of Cardiothoracic Surgery, University of California, San Diego, San Diego, CA 92103-8892

(Email: pthistlethwaite{at}ucsd.edu).

Understanding the origins and roles of cardiac progenitor cells is important for determining the pathogenesis of congenital heart diseases. In addition, use of populations of cardiac myocyte progenitors has potential for cell-based repair strategies for acquired adult heart disease.

In the last several years, there has been a surge in the understanding of cardiogenesis at the molecular level. It is now recognized that cardiac muscle cells are derived from the mesoderm, which emerges from the primitive streak during gastrulation. These cells subsequently migrate and form the primitive heart tube, which is shaped by looping and by expansion of the myocardium, ultimately leading to the formation of recognizable cardiac chambers. Several reports suggest that a hierarchal progression of stem cells from pluripotent, to multipotent, to lineage-designated, and finally to completely differentiated, exist in both the fetal and neonatal heart [1].

Recent lineage studies, based on the expression of progenitor cell–specific markers and retrospective clonal analysis in the mouse, have confirmed several cardiac lineages, based on their timing of entry into the heart and the timing of their differentiation. The first lineage is so called because it is the first to segregate from the common progenitors of all cardiac lineages. This primary heart lineage (or primary heart field) contributes cells to both ventricles, the atrioventricular canal, and both atria [2].

The secondary lineage (or secondary heart field) contributes to myocytes and vascular endothelial and smooth muscle cells of the outflow tract, right ventricle, and atria. Cells of this lineage are characterized by expression of insulin gene enhancer (isl-1) protein, a LIM homeodomain transcription factor [3].

Cells from the third and most recently classified lineage express the transcription factor, T-box 18 (Tbx-18), and migrate onto the outer surface of the heart to form the epicardium and then make contributions to myocytes, cardiac fibroblasts, and vascular smooth muscle cells in the ventricular septum and atria as well as to a small number of myocytes scattered throughout both ventricular walls [4]. The distinct embryonic origin of different cardiomyocytes provides a new framework for the study of heart development as well as congenital and adult heart disease affecting these lineages.

The article by Amir and colleagues [5] brings molecular research into the realm of human congenital heart disease in that it examines the expression of heart field markers, pluripotent stem cell markers, and markers of cellular proliferation in heart biopsy specimens of children undergoing operation, rather than in tissue from experimental animals.

Two major biases exist in this study: (1) the small sampling of right ventricular outflow tract tissue may confer a spatial sample bias for delineation of cardiac progenitor cells, and (2) the type of disease (ie, tetralogy of Fallot, and hypoplastic left heart syndrome) generally dictates the age at which repair is done and thus when a biopsy specimen becomes available. Hence, the data are unevenly distributed by repair and cluster within a narrow age range.

Nonetheless, the authors convincingly show the presence of cells expressing both pluripotent and lineage-committed markers within right ventricular outflow tract biopsy specimens. They demonstrate that the newborn heart has distinct populations of mitotically active cells that continue to reside in the right ventricle after birth, but that their density declines after the first month of life. This provocative finding suggests that the heart is still maturing and modeling in the neonatal period. Hopefully, further studies on stem cell biology and lineage fate in the heart will serve as stepping stones for harnessing the promising power of these cells to treat many forms heart disease in the future.

	References

Top References

 

1. Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis Cell 2006:1037-1048.
2. Buckingham M, Meilhac S, Zaffran S. Building the mammalian heart from two sources of myocardial cells Nature Rev Genet 2005;6:826-835.[Medline]
3. Moretti A, Caron L, Nakano A, et al. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification Cell 2006;127:1151-1165.[Medline]
4. Cai C, Martin JC, Sun Y, et al. A myocardial lineage derives from Tbx18 epicardial cells Nature 2008;454:104-109.[Medline]
5. Amir G, Ma X, Reddy VM, et al. Dynamics of human myocardial progenitor cell populations in the neonatal period Ann Thorac Surg 2008;86:1311-1320.[Abstract/Free Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Patricia A. Thistlethwaite Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Thistlethwaite, P. A. Search for Related Content PubMed PubMed Citation Articles by Thistlethwaite, P. A. Related Collections Congenital - acyanotic Molecular biology Related Article