Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Cardiovasc Res. 2010 Jul 1;87(1):92-101. doi: 10.1093/cvr/cvq033. Epub 2010 Jan 28.
During development, the heart tube grows by differentiation of Isl1(+)/Nkx2-5(+) progenitors to the arterial and venous pole and dorsal mesocardium. However, after the establishment of the heart tube, Tbx18(+) progenitors were proposed to form the Tbx18(+)/Nkx2-5(-) sinus venosus and proepicardium. To elucidate the relationship between these contributions, we investigated the origin of the Tbx18(+) sinus venosus progenitor population in the cardiogenic mesoderm and its spatial and temporal relation to the second heart field during murine heart development.
Explant culture revealed that the Tbx18(+) cell population has the potential to form Nkx2-5(-) sinus venosus myocardium. Three-dimensional reconstruction of expression patterns showed that during heart tube elongation, the Tbx18(+) progenitors remained spatially and temporally separate from the Isl1(+) second heart field, only overlapping with the Isl1(+) domain at the right lateral side of the inflow tract, where the sinus node developed. Consistently, genetic lineage analysis revealed that the Tbx18(+) descendants formed the sinus venosus myocardium, but did not contribute to the pulmonary vein myocardium that developed in the Isl1(+) second heart field. By means of DiI labelling and expression analysis, the origin of the sinus venosus progenitor population was traced to the lateral rim of splanchnic mesoderm that down-regulated Nkx2-5 expression approximately 2 days before its differentiation into sinus venosus myocardium.
Our data indicate that the cardiogenic mesoderm contains an additional progenitor subpopulation that contributes to the sinus venosus myocardium. After patterning of the cardiogenic mesoderm, this progenitor population remains spatially separated and genetically distinctive from the second heart field subpopulation.
在心脏管的发育过程中，Isl1(+)/Nkx2-5(+)祖细胞向动脉和静脉极以及背侧心内膜分化，从而使心脏管生长。然而，在心脏管形成之后，据推测 Tbx18(+)祖细胞形成 Tbx18(+)/Nkx2-5(-)窦房结和心外膜。为了阐明这些贡献之间的关系，我们研究了心生成中胚层起源的 Tbx18(+)窦房结祖细胞群体及其在鼠心脏发育过程中与第二心脏场的空间和时间关系。
外植体培养显示，Tbx18(+)细胞群体具有形成 Nkx2-5(-)窦房结心肌的潜力。表达模式的三维重建表明，在心脏管伸长期间，Tbx18(+)祖细胞在空间和时间上与 Isl1(+)第二心脏场保持分离，仅在流入道的右侧与 Isl1(+)域重叠，窦房结在该处发育。一致地，遗传谱系分析显示，Tbx18(+)后代形成窦房结心肌，但不参与在 Isl1(+)第二心脏场中发育的肺静脉心肌。通过 DiI 标记和表达分析，窦房结祖细胞群体的起源可追溯到脏层中胚层的外侧边缘，该边缘大约在分化为窦房结心肌之前 2 天下调了 Nkx2-5 的表达。
我们的数据表明，心生成中胚层包含一个额外的祖细胞亚群，该亚群有助于窦房结心肌的形成。在心生成中胚层的模式形成之后，该祖细胞群体在空间上保持分离，并且在遗传上与第二心脏场亚群不同。
