Published online before print December 4, 2008, doi: 10.1161/CIRCRESAHA.108.185843
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Submitted on December 21, 2007
Revised on October 28, 2008
Accepted on November 21, 2008
A Caudal Proliferating Growth Center Contributes to Both Poles of the Forming Heart Tube
Gert van den Berg ;
From the Heart Failure Research Center (G.v.d.B., B.A.d.B., B.v.W., P.A.J.d.B., A.T.S., J.H., J.M.R., M.J.B.v.d.H., A.F.M.M.) and the Department of Medical Informatics (B.A.d.B.), Academic Medical Center, Amsterdam, The Netherlands; and Department of Pediatrics (R.A-I., M.L.K, M.R.H.), Duke University, Durham, NC.
* To whom correspondence should be addressed. E-mail: A.F.Moorman{at}amc.uva.nl.
Recent studies have shown that the primary heart tube continues to grow by addition of cells from the coelomic wall. This growth occurs concomitantly with embryonic folding and formation of the coelomic cavity, making early heart formation morphologically complex. A scarcity of data on localized growth parameters further hampers the understanding of cardiac growth. Therefore, we investigated local proliferation during early heart formation. Firstly, we determined the cell cycle length of primary myocardium of the early heart tube to be 5.5 days, showing that this myocardium is nonproliferating and implying that initial heart formation occurs solely by addition of cells. In line with this, we show that the heart tube rapidly lengthens at its inflow by differentiation of recently divided precursor cells. To track the origin of these cells, we made quantitative 3D reconstructions of proliferation in the forming heart tube and the mesoderm of its flanking coelomic walls. These reconstructions show a single, albeit bilateral, center of rapid proliferation in the caudomedial pericardial back wall. This center expresses Islet1. Cell tracing showed that cells from this caudal growth center, besides feeding into the venous pole of the heart, also move cranially via the dorsal pericardial mesoderm and differentiate into myocardium at the arterial pole. Inhibition of caudal proliferation impairs the formation of both the atria and the right ventricle. These data show how a proliferating growth center in the caudal coelomic wall elongates the heart tube at both its venous and arterial pole, providing a morphological mechanism for early heart formation.
Key words: cardiovascular development • proliferation • heart fields • Islet1 • bromodeoxy uridine • quantitative 3D construction
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