Multipotent Islet-1 Cardiovascular Progenitors in Development and Disease

Abstract

During the past several years, advances at the intersection of cardiovascular development and heart stem cell biology have begun to reshape our view of the fundamental logic that drives the formation of discrete tissue components in the mammalian heart. Although many of the critical genes that control cardiac myogenesis have been identified, our understanding of how a highly diverse and specialized subset of heart cell lineages arises from mesodermal precursors and is subsequently assembled into distinct muscle chambers, coronary arterial tree and large vessels, valvular tissue, and conduction system/pacemaker cells remains at a relatively primitive stage. Recent studies have uncovered a diverse group of closely related heart progenitors that are central in controlling and coordinating these complex steps of cardiogenesis. Understanding the pathways that control their formation, renewal, and subsequent conversion to specific differentiated progeny forms the underpinning for unraveling the pathways for congenital heart disease and has direct relevance to cardiovascular regenerative medicine. This current brief review highlights the discovery and delineation of the role of Islet-1 cardiovascular progenitors in the generation of diverse heart cell lineages and how the implications of these findings are revising our classification and thinking about congenital heart disease in general.

Islet-1 promotes the cardiac-specific differentiation of mesenchymal stem cells through the regulation of histone acetylation

“…Various types of congenital heart disease can be caused by Islet-1 insufficiency (14,15,29). Islet-1 has also been recognized as a marker of cardiovascular progenitors (16,30). Islet-1-positive progenitors can differentiate into diverse cardiovascular cell lineages.…”

“…However, Islet-1, a subtype of the LIM-homeodomain transcription factor (LIM-HD) subfamily, contains a DNA binding site and two LIM domains, and is able to bind with GCN5, which is a member of the HAT family involved in cardiomyocyte, hepatocyte, as well as bone and neuron differentiation (12–14). Several studies have demonstrated that Islet-1 is crucial to cardiac development and cardiomyocyte differentiation (15–16). Thus, we hypothesized that Islet-1 is a key factor during the process of the specific differentiation of MSCs into cardiomyocyte-like cells and that it exerts its effects possibly through modifications in histone acetylation and deacetylation.…”

An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood

“…Timing is also relevant to our appreciation of the etiologies of congenital heart defects in humans given the importance of sequential differentiation of the first heart field (FHF) and the second heart field (SHF) (Bruneau, 2008; Nakano et al, 2008; Srivastava and Olson, 2000). Nkx2-5 is expressed in FHF and SHF of mouse and zebrafish embryos (Guner-Ataman et al, 2013; Stanley et al, 2002) and mutations in both lineages result in CHD (Lyons et al, 1995; Prall et al, 2007; Tanaka et al, 1999a).…”

The Histone Methyltransferase Inhibitor BIX01294 Enhances the Cardiac Potential of Bone Marrow Cells

“…Mesp1 is a bHLH transcription factor that emerges in the early embryo within the nascent mesoderm, most prominently in precardiac tissue, and is proposed to play a key role in the cardiac lineage specification [36][37][38]. Islet1 is considered the defining marker of progenitor cells in the secondary heart field [39,40], although more recent data indicated that islet1 is also exhibited by progenitors within the primary heart field [41,42].…”