Search

The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The epicardium harbors a population of progenitor cells that undergo epithelial-to-mesenchymal transition displaying characteristic conversion of planar epithelial cells into multipolar and invasive mesenchymal cells before differentiating into nonmyocyte cardiac lineages, such as vascular smooth muscle cells, pericytes, and fibroblasts. The epicardium is also a source of paracrine cues that are essential for fetal cardiac growth, coronary vessel patterning, and regenerative heart repair. Although the epicardium becomes dormant after birth, cardiac injury reactivates developmental gene programs that stimulate epithelial-to-mesenchymal transition; however, it is not clear how the epicardium contributes to disease progression or repair in the adult. In this review, we will summarize the molecular mechanisms that control epicardium-derived progenitor cell migration, and the functional contributions of the epicardium to heart formation and cardiomyopathy. Future perspectives will be presented to highlight emerging therapeutic strategies aimed at harnessing the regenerative potential of the fetal epicardium for cardiac repair.

The Permeability Transition Pore Controls Cardiac Mitochondrial Maturation and Myocyte Differentiation Hom et al Dev Cell. 2011;21:469–478. The behavior of the mitochondrial permeability transition pore has been linked to mitochondrial maturation underlying cardiomyocyte differentiation in the embryo. Mitochondrial signaling in heart development has direct implications for cardiogenesis and stem cell lineage specification. Heart formation requires maturation and integration of multiple systems to support development of the contractile apparatus in the nascent cardiomyocyte. Although a number of transcriptional networks that facilitate cardiogenesis have been mapped, master regulators of heart development remain elusive. A recent report highlights mitochondria, and more specifically the mitochondrial permeability transition pore (mPTP), as a gating mechanism underlying differentiation in the developing heart,1 implicating cross-talk between genetic and metabolic signaling. Immature mitochondria of early embryonic hearts must transition into more complex structures to ensure proficient and energetically competent cardiac development.2–4 Developmental restructuring is recapitulated during spontaneous differentiation of stem cells, where pluripotent gene downregulation accelerates mitochondria DNA replication to promote mitochondrial biogenesis associated with lineage specification.2–6 Cardiomyocytes isolated from day 9.5 embryos (e9.5) harbor few fragmented mitochondria, with poorly defined and unorganized cristae, which undergo elaborate maturation and by day e13.5 evolve into filamentous networks of elongated and branched mitochondria with abundant and organized cristae.1 Moreover, mitochondria expansion from a predominately perinuclear localization to an extensive configuration across the cell facilitates energy supply and transfer between cellular compartments.1,2,4,7–9 Mitochondrial structure and function are markers of differentiation capacity. Cells with less perinuclear mitochondria have greater spontaneous differentiation,10 and those with low mitochondrial membrane potential show greater propensity for mesodermal differentiation.11 Remodeling of the mitochondrial infrastructure matches the evolving bioenergetic demands, with contractile function driving the requirement for efficient oxidative ATP generation in the developing heart.2,7,12 Hom et al now demonstrate that modulators …

The armadillo-related protein β-catenin has multiple functions in cardiac tissue homeostasis: stabilization of β-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell–cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of β-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible αMHC-CrePR1 transgene was used to induce β-catenin depletion (loxP-flanked exons 3 to 6, β-cat Δex3–6 mice) or stabilization (loxP-flanked exon 3, β-cat Δex3 mice). Levels of β-catenin were altered both in membrane and nuclear extracts. Analysis of the β-catenin target genes Axin2 and Tcf-4 confirmed increased β-catenin–dependent transcription in β-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. β-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with β-catenin depletion. In contrast, mice with stabilized β-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing β-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in β-catenin–stabilized mice. These data suggest that β-catenin downregulation is required for adaptive cardiac hypertrophy.

The delineation of the mechanisms that regulate cardiac gene expression is central to our understanding of cardiac growth and development. Much progress has been made toward the identification of factors involved in tissue-restricted gene expression, especially in skeletal muscle cells. However, the mechanisms regulating the expression of cardiac-specific genes remain less well understood. Certain homeodomain proteins have been implicated in commitment to the cardiac phenotype. Among the best characterized are the murine proteins Csx, Nkx-2.5, and Nkx-2.6, related to the protein tinman, which is essential for heart formation in Drosophila . The expression of these genes precedes that of cardiac-specific genes and is therefore believed to play a critical role in the development of the heart. The GATA proteins are a family of zinc finger proteins that are also expressed early in cardiac development and may act separately from, or in concert with, the homeodomain proteins as crucial regulators of heart development. The myosin heavy and light chain genes, the actin genes, the troponin genes, and the atrial natriuretic factor and muscle creatine kinase genes have served as excellent paradigms for the study of cardiac gene expression. Although differences in cis -acting elements and their behavior in binding assays have been observed between different genes, there exist similarities that are noteworthy. In this review, we will discuss the factors involved in the regulation of cardiac-specific gene expression in an attempt to provide a better understanding of the process of cardiogenesis.

Transcription factors can regulate the expression of other genes in a tissue-specific and quantitative manner and are thus major regulators of embryonic developmental processes. Several transcription factors that regulate cardiac genes specifically have been described, and the recent discovery that dominant inherited transcription factor mutations cause congenital heart defects in humans has brought direct medical relevance to the study of cardiac transcription factors in heart development. Although this field of study is extensive, several major gaps in our knowledge of the transcriptional control of heart development still exist. This review will concentrate on recent developments in the field of cardiac transcription factors and their roles in heart formation.

Over the last 10 years, significant progress has been made in the understanding of molecular and genetic determinants of heart formation. An ever growing number of genes have been identified that are required for cardiogenesis, as evidenced by severe abnormalities in cardiac development produced by inactivation in the mouse or inhibition of gene function in other model organisms.1 In general, scientists have identified these genes because of their expression in early cardiac tissues or because of the severe phenotype produced by mutation or inactivation. Gross abnormalities of cardiac development lead to embryonic demise either during midgestation or in the peripartum period, and the underlying severe defects in cardiac structure or function have been relatively easy to determine and describe.1 2 3 Similar defects in the human versions of these genes may account for embryonic lethal forms of human congenital heart disease. It has been hypothesized that hypomorphic mutations or reduction in gene dosage may result in less severe forms of congenital heart disease, such as those seen in surviving newborns and adults. Alternatively, clinically relevant cardiovascular developmental defects affecting infants and adults generally may result from mutations in genes entirely unrelated to those critical during early stages of cardiac specification and heart morphogenesis, making these factors less attractive for intensive study as disease-causing genes. Data to support the former hypothesis have recently come to light. Perhaps the most intriguing example comes from the study of a mammalian homologue of a gene first described in the fruit fly, Drosophila melanogaster . This organism has an open circulation in which hemolymph is distributed with the assistance of a contracting dorsal aorta. Although structurally dissimilar from the …