Article

Mesp1 at the Heart of Mesoderm Lineage Specification

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell stem cell (Impact Factor: 22.15). 08/2008; 3(1):1-2. DOI: 10.1016/j.stem.2008.06.017
Source: PubMed

ABSTRACT Stem cell-based cardiac regeneration requires a detailed understanding of the factors that induce cardiac lineage commitment. In this issue of Cell Stem Cell, Lindsley et al. (2008) and Bondue et al. (2008) use embryonic stem cells to identify a key role for Mesp1 in this process.

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    • "Markers such as Mesp1 and Mesp2 have been used to identify these earliest cardiac and skeletal precursors (Lindsley et al., 2008; Wu et al., 2008). When mesodermal precursors restrict their fate to cardiovascular and hematopoietic lineages, they begin to express Mesp1 and Flk1 (Wu, 2008). Flk1 is used to denote primitive precursors for cardiovascular cells (Kattman et al., 2006) and has been detected in undifferentiated embryonic stem cells (Kouskoff et al., 2005). "
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    • "The repressor ripply1 was normally detected in control embryos (E) and cyclopamine-treated embryos (J). the murine Mesp1 and Mesp2 gene (Saga et al., 1996 and 1997; Sawada et al., 2000). Mesp1 plays an important role during early cardiac mesoderm lineage specification (Saga et al., 1999; Wu, 2008). However, the role of Mesp1 during somitogenesis is little studied. "
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    ABSTRACT: The transcription factor FoxD5 is expressed in the paraxial mesoderm of zebrafish. However, the roles of FoxD5 in anterior pre-somitic mesoderm (PSM) during somitogenesis are unknown. We knocked down FoxD5 in embryos, which resulted in defects of the newly formed somites, including loss of the striped patterns of anterior-posterior polarity genes deltaC, notch2, notch3 and EphB2a, as well as the absence of mespa expression in S-I. Also, the expression of mespb exhibited a 'salt and pepper' pattern, indicating that FoxD5 is necessary for somite patterning in anterior PSM. Embryos were treated with SU5402, an Fgf receptor (FGFR) inhibitor, resulting in reduction of FoxD5 expression. This finding was consistent with results obtained from Tg(hsp70l:dnfgfr1-EGFP)pd1 embryos, whose dominant-negative form of FGFR1 was produced by heat-induction. Loss of FoxD5 expression was observed in the embryos injected with fgf3-/fgf8-double-morpholinos (MOs). Excessive FoxD5 mRNA could rescue the defective expression levels of mespa and mespb in fgf3-/fgf8-double morphants, suggesting that Fgf signaling acts as an upstream modulator of FoxD5 during somitogenesis. We concluded that FoxD5 is required for maintaining anterior-posterior polarity within a somite and that the striped pattern of FoxD5 in anterior PSM is mainly regulated by Fgf. An Fgf-FoxD5-Mesps signaling network is therefore proposed.
    Developmental Biology 10/2009; 336(2):232-45. DOI:10.1016/j.ydbio.2009.10.001 · 3.64 Impact Factor
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    ABSTRACT: AIMS: The proliferative potential of pluripotent stem cell-derived cardiomyocytes is limited, and reasonable yields for novel therapeutic options have yet to be achieved. In addition, various clinical applications will require the generation of specific cardiac cell types. Whereas early cardiovascular precursors appear to be important for novel approaches such as reseeding decellularized hearts, direct cell transplantation may require ventricular cells. Our recent work demonstrated that MesP1 represents a master regulator sufficient to induce cardiovasculogenesis in pluripotent cells. This led to our hypothesis that 'forward programming' towards specific subtypes may be feasible via overexpression of distinct early cardiovascular transcription factors. METHODS AND RESULTS: Here we demonstrate that forced expression of Nkx2.5 similar to MesP1 is sufficient to enhance cardiogenesis in murine embryonic stem cells (mES). In comparison to control transfected mES cells, a five-fold increased appearance of beating foci was observed as well as upregulated mRNA and protein expression levels. In contrast to MesP1, no increase of the endothelial lineage within the cardiovasculogenic mesoderm was observed. Likewise, Flk-1, the earliest known cardiovascular surface marker, was not induced via Nkx2.5 as opposed to MesP1. Detailed patch clamping analyses showed electrophysiological characteristics corresponding to all subtypes of cardiac ES cell differentiation in Nkx2.5 as well as MesP1 programmed embryoid bodies, but fractions of cardiomyocytes had distinct characteristics: MesP1 forced the appearance of early/intermediate type cardiomyocytes in comparison to control transfected ES cells whereas Nkx2.5 led to preferentially differentiated ventricular cells. CONCLUSION: Our findings show proof of principle for cardiovascular subtype-specific programming of pluripotent stem cells and confirm the molecular hierarchy for cardiovascular specification initiated via MesP1 with differentiation factors such as Nkx2.5 further downstream.