A model for NO-dependent epigenetic effect during ESC vascular differentiation. NO may be produced both by ligand-activated receptors and environmental cues (e.g. shear stress), which activate the PI3K/Akt pathway leading to eNOS phosphorylation. Cytosolic NO, in turn, induces class II HDACs nuclear translocation via PP2A activation and post-translational modification (mainly tyrosine nitration and S-nitrosylation) of transcription factors. NO may exert its function in the nucleus after diffusion from the cytosol. Further, it may be directly produced by the nuclear eNOS (ref). In the nuclear compartment, NO post-translationally modify HDAC2 and transcription factors. Altogether, these processes lead both to the repression of stem and non-mesodermal genes and to the activation of vascular genes. Tyr-nitration, tyrosine nitration; BH4, tetrahydrobiopterin.
Cardiac cell types derived from multipotent progenitors. Differentiated cardiac cell types are marked by indicated genes (green). Recently, several factors have been defined as master regulators for cardiomyogenesis (red). The combination of Tbx5, Gata4, and Baf60c induces direct differentiation of mesodermal cells into ectopic beating myocytes, bypassing the cardiac progenitor state.55 Tbx5, Gata4, and Mef2c together can also induce cardiomyocytes from fibroblasts.91 Factors for direct induction of other cardiac cell types are currently unknown (question marks).
Schematic illustration of progressive contractile and conductive maturation during cardiogenesis. Schematic representation of the different stages of mouse cardiac development: cardiac crescent (A) straight tube, (B) looping, (C) embryonic, (D) foetal, (E), and adult (F) heart. The progressive formation of contractile and cell-to-cell conductive elements is depicted in (A′)–(F′). Cell-to-cell wiring illustrates the progressive alignment of connexins during cardiomyocyte differentiation. Similarly, progressive development of the cardiac action potential and the ECG recordings are illustrated in (A″)–(F″) and (A′′′)–(F′′′), respectively. Cardiac action potential diversity between conductive and working myocardium is illustrated at embryonic (E8.5) stages and between nodal, atrial, and ventricular myocytes from late embryonic stages (E9.5) onwards. Note that while cardiac action potential configuration resembles that of man, yet significant differences are observed in other species. Asterisks demarcate those stages and pathways in which impaired expression and/or function has been documented on Pitx2 deficiency. FHF, first heart field; SHF, second heart field; oft, outflow; ift, inflow; pv, primitive ventricle; rv, right ventricle; ra, right atrium; lv, left ventricle; la, left atrium; avc, atrioventricular canal.
Biphasic development of the ventricular conduction system.
The ventricular conduction system controls the propagation of electrical activity through the heart to coordinate cardiac contraction. To define the lineage relationship between cells of the murine ventricular conduction system and surrounding working myocytes, we used a retrospective clonal analysis to study the properties of clonally related cells. (A) Retrospective nlaacZ clonal analysis of the ventricular conduction system demonstrates two types of clusters. Mixed clusters composed of conductive and working myocytes reveal that both cell types develop from common progenitor cells, while unmixed clusters composed of either conductive or working myocytes show that proliferation continues after lineage restrictions. (B) The relative small size of unmixed conductive clusters in comparison to mixed clusters or to unmixed contractile clusters shows that proliferation follows cell lineage restriction and that proliferation is more limited for conductive cells than for working cardiomyocytes, respectively. This established that the ventricular conduction system developed by a biphasic mode of development: differentiation from a common myogenic progenitor followed by limited proliferation of conductive myocytes.
The relationship between glomerulus and epicardium has been postulated via pro-epicardial cells. Pro-epicardium gives rise to epicardial progenitor cells. Epicardium has an essential modulating role in the differentiation of the compact ventricular layer of the myocardium and the development of cardiac vessels. Moreover, the epicardial progenitor cells have been shown to differentiate into the pronephric external glomerulus (PEG), a structure composed of capillary networks, mesangial cells, and podocytes in vertebrates.