Early lineage restriction in temporally distinct populations of Mesp1 progenitors during mammalian heart development

Abstract

Cardiac development arises from two sources of mesoderm progenitors, the first heart field (FHF) and the second (SHF). Mesp1 has been proposed to mark the most primitive multipotent cardiac progenitors common for both heart fields. Here, using clonal analysis of the earliest prospective cardiovascular progenitors in a temporally controlled manner during early gastrulation, we found that Mesp1 progenitors consist of two temporally distinct pools of progenitors restricted to either the FHF or the SHF. FHF progenitors were unipotent, whereas SHF progenitors were either unipotent or bipotent. Microarray and single-cell PCR with reverse transcription analysis of Mesp1 progenitors revealed the existence of molecularly distinct populations of Mesp1 progenitors, consistent with their lineage and regional contribution. Together, these results provide evidence that heart development arises from distinct populations of unipotent and bipotent cardiac progenitors that independently express Mesp1 at different time points during their specification, revealing that the regional segregation and lineage restriction of cardiac progenitors occur very early during gastrulation.

Id genes are essential for early heart formation

“…Collectively, these observations suggest that only the most anterior subset of cardiac progenitors require Id1-4 activity for their specification. Consistent with our findings, Lescroart et al (2014) have shown recently that early Mesp1-expressing mesoderm progenitors (around E6.5), which contribute to first heart field derivatives, express high levels of Id1. In contrast, late Mesp1-expressing cells (around E7.5), which contribute to second heart field derivatives, express low levels of Id1 (see the Supplemental Material of Lescroart et al 2014).…”

“…Consistent with our findings, Lescroart et al (2014) have shown recently that early Mesp1-expressing mesoderm progenitors (around E6.5), which contribute to first heart field derivatives, express high levels of Id1. In contrast, late Mesp1-expressing cells (around E7.5), which contribute to second heart field derivatives, express low levels of Id1 (see the Supplemental Material of Lescroart et al 2014). Moreover, we show that human iMPs upregulate first heart field markers (HCN4 and TBX5) during cardiac differentiation, while second heart field markers (ISL1 and SIX2) are down-regulated (Supplemental Fig.…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…2D,E, arrows). These new progenitors have their origins in a distinct heart progenitor field termed the second heart field (SHF), which probably exits the primitive streak somewhat later than FHF progenitors (Lescroart et al, 2014). SHF cells are therefore delayed in their differentiation.…”

“…However, recent lineage-tracing studies have shown that although FHF and SHF cells arise from a common progenitor, probably in the pre-gastrulation embryo, their territories become geographically separate (Ali et al, 2014;Buckingham et al, 2005;Meilhac et al, 2004). FHF progenitors that form the primary heart tube and future left ventricle (Buckingham et al, 2005;Lescroart et al, 2014) are unipotent for cardiomyocytes or endothelial cell fates (Cohen-Gould and Mikawa, 1996;Lescroart et al, 2014). By contrast, SHF cells exiting the primitive streak later and contributing to other regions of the heart are either unipotent or bipotent for cardiomyocyte and endothelial cells, or cardiomyocytes and smooth muscle cells.…”

“…2D) arise from a unique set of progenitors termed the first heart field (FHF), which occupy a distinct anterior-lateral territory within the cardiac crescent ( Fig. 2C) (Buckingham et al, 2005;Lescroart et al, 2014), distinguished by expression of the gene for hyperpolarizationactivated cyclic nucleotide-gated channel 4 (Hcn4) (Liang et al, 2013). The primary heart tube acts as a type of scaffold for heart tube elongation through the addition of new myocardial, endocardial and smooth muscle cell progenitors to its inflow and outflow poles (Fig.…”