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Cardiac Cell Specification by Defined Factors

  • Yuika Morita
  • Jun Takeuchi
Open Access
Conference paper
  • 387 Downloads

Abstract

Our previous study has shown that Tbx5-Gata4-Baf60c-induced functional cardiomyocytes via the ectopic expression of Nkx2-5/Islet1 in the mesodermal cells, but not in the endodermal/ectodermal cells [1, 2] (Fig. 57.1). Mesp1 is one of the major transcriptional regulators specifying the mesodermal lineage, but it also induces skeletal muscle, hematopoietic and vascular cells as well as cardiac cells [3–5]. Eomesodermin (Eomes), an upstream player of Mesp1, regulates mesodermal cell lineages, but it does not have a potential for specification of cardiac cell fate from cardiovascular lineages either [6]. Therefore, the study of cardiac cell fate specification from the embryonic stem cells by the defined factors still remains at least two major questions.

Our previous study has shown that Tbx5-Gata4-Baf60c-induced functional cardiomyocytes via the ectopic expression of Nkx2-5/Islet1 in the mesodermal cells, but not in the endodermal/ectodermal cells [1, 2] (Fig. 57.1). Mesp1 is one of the major transcriptional regulators specifying the mesodermal lineage, but it also induces skeletal muscle, hematopoietic and vascular cells as well as cardiac cells [3, 4, 5]. Eomesodermin (Eomes), an upstream player of Mesp1, regulates mesodermal cell lineages, but it does not have a potential for specification of cardiac cell fate from cardiovascular lineages either [6]. Therefore, the study of cardiac cell fate specification from the embryonic stem cells by the defined factors still remains at least two major questions.
  1. 1.

    How the cardiac lineage is committed from the mesoderm via repressing skeletal muscle, hematopoietic and vascular cell fates?

     
  2. 2.

    Are there any factors specifying the cardiac lineage directly from the undifferentiated stem cells?

     
Fig. 57.1

The defined factors for cardiogenesis

To disclose these questions, we performed RNA sequencing from the anterior field at the early cardiac crescent stage, and we identified Sall1 gene as a suitable key regulator for the cardiac cell lineage [7]. Overexpression of Sall1 in mouse ES accelerated cardiogenesis and also promoted cardiac cell fate in human iPS cells with upregulation of several cardiac transcriptional genes (ISLET1/NKX2-5/MEF2C) and sarcomeric genes (TNNT2/MYL7/MYH6/MYH7). Sall1 also acts as a modulator to recruit the histone-modification/the chromatin remodeling factors and the other transcriptional factors to commit the cardiac cell fate. Interestingly, permanent expression of Sall1 in differentiating human iPS cells increased the number of cardiac progenitor cells [7] (Fig. 57.2). These data suggest that Sall1 acts as a key factor to promote and maintain the cardiac progenitor cell phase from undifferentiating stem cells, and down-regulation of Sall1 expression after induction of cardiac progenitor cells is necessary to shift the cell fate to cardiomyocyte differentiation.
Fig. 57.2

The critical expression of Sall1 for promoting cardiogenesis

Our data just show that a novel gene, Sall1, programs cardiac cell fate and accelerates cardiogenesis, but this factor may act as a defined player for the cardiac cell fate with and the other transcriptional factors to define. Thus, the study for isolation of in vivo Sall1 partners and establishment of its regulation will give us the next window for the program/reprogram research (Fig. 57.1).

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© The Author(s) 2020

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Authors and Affiliations

  • Yuika Morita
    • 1
    • 2
  • Jun Takeuchi
    • 1
  1. 1.MRITokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of CardiologyKeio UniversityTokyoJapan

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