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Review
. 2011 Jun;240(6):1322-34.
doi: 10.1002/dvdy.22650. Epub 2011 May 2.

Myocyte proliferation in the developing heart

David Sedmera  1 , Robert P Thompson
Affiliations
Review

Myocyte proliferation in the developing heart

David Sedmera et al. Dev Dyn. 2011 Jun.

Abstract

Regulation of organ growth is critical during embryogenesis. At the cellular level, mechanisms controlling the size of individual embryonic organs include cell proliferation, differentiation, migration, and attrition through cell death. All these mechanisms play a role in cardiac morphogenesis, but experimental studies have shown that the major determinant of cardiac size during prenatal development is myocyte proliferation. As this proliferative capacity becomes severely restricted after birth, the number of cell divisions that occur during embryogenesis limits the growth potential of the postnatal heart. We summarize here current knowledge concerning regional control of myocyte proliferation as related to cardiac morphogenesis and dysmorphogenesis. There are significant spatial and temporal differences in rates of cell division, peaking during the preseptation period and then gradually decreasing toward birth. Analysis of regional rates of proliferation helps to explain the mechanics of ventricular septation, chamber morphogenesis, and the development of the cardiac conduction system. Proliferation rates are influenced by hemodynamic loading, and transduced by autocrine and paracrine signaling by means of growth factors. Understanding the biological response of the developing heart to such factors and physical forces will further our progress in engineering artificial myocardial tissues for heart repair and designing optimal treatment strategies for congenital heart disease.

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Figures

Figure 1
Figure 1
A. Label dilution of [3H] thymidine in chick embryonic heart. Label was applied on ED2, and the heart sampled at ED10. Most of the radiolabel detected by autoradiography is retained in the ventricular conduction system, while more rapidly dividing working myocardium diluted label through many rounds of cell division. Ao, aorta, LBB, left bundle branch, LV, left ventricle, RV, right ventricle. From Thompson et al., 2000. B. Illustration of different immunohistochemical techniques for myocyte proliferation. Bromodeoxyuridine labeling (secondary antibody in the green channel) gives all-or-nothing signal, and labels only cells passing through S-phase during the labeling period (2). Proliferating cell nuclear antigen (red channel) lingers in the nuclei for longer time, and labels also cells that recently completed karyokinesis or cytokinesis (1, 1′). Unlabeled nuclei (without counterstaining) appear as oval shadows in the autofluorescent cytoplasm (3). Sample from neonatal pig myocardium labeled for 2 hours with bromodeoxyuridine. C. Saturation labeling in the fetal heart. Sections from rat embryonic heart labeled via Alzet osmotic mini-pump from ED17.5 to ED18.5. While almost all nuclei are labeled in the compact myocardium (Co), the trabeculae (Tr) show much lower labeling. Central conduction system in the interventricular septum (IVS) stands out by its paucity of label. Arrow points to left bundle branch (compare with Figure 1, where this structure, in a different species, is also distinguished by its low proliferation). Note also that the working myocardium of the interventricular septum shows similar labeling intensity as the compact myocardium (see also Figure2B for comparison with fetal chick data).
Figure 2
Figure 2
Quantitative data of developmental trends in myocyte proliferation. A. Data from the entire chick embryonic heart (labeling with radioactive thymidine for 45 minutes show the peak in labeling index between embryonic day 3 and 4. B. Historical data of mitotic counts from chick embryonic heart showing similar declining trend from peak at embryonic day 4 towards hatching in both ventricles. This graph also shows clearly that the forming interventricular septum is distinguished by its low proliferative activity, while after completion of septation it behaves as the rest of the working myocardium. C. Regional differences in myocyte labeling in developing rat heart. Note the difference between the compact zone and the trabeculae as well as gradual decrease towards birth. D. Values from 2h bromodeoxyuridine labeling in the preseptation chick heart show decreasing gradient between the compact myocardium and trabeculae as well as decline in labeling with advancing development. The trends are identical in both left and right ventricle.
Figure 3
Figure 3
Differences in myocyte proliferation in the compact zone at the organ level. Two proliferative centers (black) in the apices of prospective left and right ventricle, together with lower activity in the interventricular septum (*), were noted by Rychter et al. (1979). Similar data (high proliferative activity in red, slowly dividing septum - *), together with regions of low myocyte proliferation in the atrioventricular canal and the outflow tract (blue) were recently reported by van den Berg et al (2009).
Figure 4
Figure 4
Persistence of labeled cells in the ventricular conduction system in the chick. There is a gradual decrease in heavily labeled cells (over 10 grains per nucleus) with postnatal development, but both these and less intensively labeled cells can be found into adulthood, ten months after hatching. Values are means from three hearts, counting grains per nucleus in every tenth section. (See Thompson et al., 2000).
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