Mesp1 Coordinately Regulates Cardiovascular Fate Restriction and Epithelial-Mesenchymal Transition in Differentiating ESCs

Abstract

SUMMARY Wnt signaling is required for development of mesoderm-derived lineages and expression of transcription factors associated with the primitive streak. In a functional screen, we examined the mesoderm-inducing capacity of transcription factors whose expression was Wnt-dependent in differentiating ESCs. In contrast to many inactive factors, we found that mesoderm posterior 1 (Mesp1) promoted mesoderm development independently of Wnt signaling. Transient Mesp1 expression in ESCs promotes changes associated with epithelial-mesenchymal transition (EMT) and induction of Snai1, consistent with a role in gastrulation. Mesp1 expression also restricted the potential fates derived from ESCs, generating mesoderm progenitors with cardiovascular, but not hematopoietic, potential. Thus, in addition to its effects on EMT, Mesp1 may be capable of generating the recently identified multipotent cardiovascular progenitor from ESCs in vitro.

Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation

“…The increase in cells expressing Flk1 and PDGFRa after Mesp1 expression (Lindsley et al, 2008) sug gests that Mesp1 expression can promote MCP specification. To determine whether Mesp1 rapidly promotes MCP specification, we assessed the relative frequency of CXCR4/PDGFRa/Flk1 TP cells at different early time points after Mesp1 expression a certain number of genes were found to be up regulated in only one of the two replicates, probably because of low level expression, but were confirmed by RT PCR on different biolog ical replicates.…”

“…Although genetic mutation of Mesp1 in mice does not lead to the absence of cardiac and vascular cells, possibly because the compensation is mediated by the massive up regulation of its closest homologue Mesp2 (Saga et al, 1999;Kitajima et al, 2000), the combined deletion of Mesp1 and Mesp2 leads to the absence of mesoderm and car diac specification . Recently, we and others have shown that Mesp1 overexpression greatly promotes the generation of multiple cardiovascular cell lineages during ESC differentiation, including derivatives of FHF and SHF pro genitors (Bondue et al, 2008;David et al, 2008;Lindsley et al, 2008). Transcriptional profiling of Mesp1 expressing cells combined with chromatin immunoprecipitation experiments revealed that Mesp1 directly and rapidly induces the expression of many transcription factors implicated in cardiovascular spec ification.…”

“…Transcriptional profiling of Mesp1 expressing cells combined with chromatin immunoprecipitation experiments revealed that Mesp1 directly and rapidly induces the expression of many transcription factors implicated in cardiovascular spec ification. (Bondue et al, 2008;Lindsley et al, 2008).…”

Eomesodermin induces Mesp1 expression and cardiac differentiation from embryonic stem cells in the absence of Activin

“…Here we investigated the role of Eomes in early cell fate decisions during mouse ESC differentiation, and found that in the absence of extrinsic signals, Eomes promoted the formation of cardiac mesoderm by stimulating the expression of Mesp1, a transcription factor known to have a key role in the specification of cardiovascular mesoderm [24][25][26][27][28]. High levels of Activin decreased the ability of Eomes to stimulate Mesp1 expression, and instead led to the induction of endodermal fate.…”

miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification

“…Mesp1 drives ES cells (ESCs) toward the cardiac fate. Transient expression of Mesp1 accelerated and enhanced the appearance of cardiac progenitors (19)(20)(21)(22). Despite its pivotal role in cardiogenesis, its expression is highly transitory.…”