Dataset Information

Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein- and fibroblast growth factor-signaling pathways.

ABSTRACT: The epicardium contributes to the majority of nonmyocardial cells in the adult heart. Recent studies have reported that the epicardium is derived from Nkx2.5-positive progenitors and can differentiate into cardiomyocytes. Not much is known about the relation between the myocardial and epicardial lineage during development, whereas insights into these embryonic mechanisms could facilitate the design of future regenerative strategies.Acquiring insight into the signaling pathways involved in the lineage separation leading to the differentiation of myocardial and (pro)epicardial cells at the inflow of the developing heart.We made 3D reconstructions of Tbx18 gene expression patterns to give insight into the developing epicardium in relation to the developing myocardium. Next, using DiI tracing, we show that the (pro)epicardium separates from the same precursor pool as the inflow myocardium. In vitro, we show that this lineage separation is regulated by a crosstalk between bone morphogenetic protein (BMP) signaling and fibroblast growth factor (FGF) signaling. BMP signaling via Smad drives differentiation toward the myocardial lineage, which is inhibited by FGF signaling via mitogen-activated protein kinase kinase (Mek)1/2. Embryos exposed to recombinant FGF2 in vivo show enhanced epicardium formation, whereas a misbalance between FGF and BMP by Mek1/2 inhibition and BMP stimulation causes a developmental arrest of the epicardium and enhances myocardium formation at the inflow of the heart.Our data show that FGF signaling via Mek1/2 is dominant over BMP signaling via Smad and is required to separate the epicardial lineage from precardiac mesoderm. Consequently, myocardial differentiation requires BMP signaling via Smad and inhibition of FGF signaling at the level of Mek1/2. These findings are of clinical interest for the development of regeneration-based therapies for heart disease.

SUBMITTER: van Wijk B

PROVIDER: S-EPMC2861358 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein- and fibroblast growth factor-signaling pathways.

van Wijk Bram B van den Berg Gert G Abu-Issa Radwan R Barnett Phil P van der Velden Saskia S Schmidt Martina M Ruijter Jan M JM Kirby Margaret L ML Moorman Antoon F M AF van den Hoff Maurice J B MJ

Circulation research 20090723 5

<h4>Rationale</h4>The epicardium contributes to the majority of nonmyocardial cells in the adult heart. Recent studies have reported that the epicardium is derived from Nkx2.5-positive progenitors and can differentiate into cardiomyocytes. Not much is known about the relation between the myocardial and epicardial lineage during development, whereas insights into these embryonic mechanisms could facilitate the design of future regenerative strategies.<h4>Objective</h4>Acquiring insight into the s ...[more]

PMID: 19628790

Similar Datasets

Project description:Iron is essential to many biological processes but its poor solubility in aerobic environments restricts its bioavailability. To overcome this limitation, bacteria have evolved a variety of strategies, including the production and secretion of iron-chelating siderophores. Here, we describe the discovery of four series of siderophores from Streptomyces ambofaciens ATCC23877, three of which are unprecedented. MS/MS-based molecular networking revealed that one of these series corresponds to acylated desferrioxamines (acyl-DFOs) recently identified from S. coelicolor. The remaining sets include tetra- and penta-hydroxamate acyl-DFO derivatives, all of which incorporate a previously undescribed building block. Stable isotope labeling and gene deletion experiments provide evidence that biosynthesis of the acyl-DFO congeners requires unprecedented crosstalk between two separate non-ribosomal peptide synthetase (NRPS)-independent siderophore (NIS) pathways in the producing organism. Although the biological role(s) of these new derivatives remain to be elucidated, they may confer advantages in terms of metal chelation in the competitive soil environment due to the additional bidentate hydroxamic functional groups. The metabolites may also find application in various fields including biotechnology, bioremediation, and immuno-PET imaging.IMPORTANCEIron-chelating siderophores play important roles for their bacterial producers in the environment, but they have also found application in human medicine both in iron chelation therapy to prevent iron overload and in diagnostic imaging, as well as in biotechnology, including as agents for biocontrol of pathogens and bioremediation. In this study, we report the discovery of three novel series of related siderophores, whose biosynthesis depends on the interplay between two NRPS-independent (NIS) pathways in the producing organism S. ambofaciens-the first example to our knowledge of such functional cross-talk. We further reveal that two of these series correspond to acyl-desferrioxamines which incorporate four or five hydroxamate units. Although the biological importance of these novel derivatives is unknown, the increased chelating capacity of these metabolites may find utility in diagnostic imaging (for instance, 89Zr-based immuno-PET imaging) and other applications of metal chelators.

Project description:During cardiogenesis, a subset of epicardial cells undergoes epithelial-mesenchymal-transition (EMT) and the resulting epicardial-derived cells (EPDCs) contribute to the formation of coronary vessels. Our previous data showed hypoxia inducible factor-1α (HIF-1α) expression at specific sites within the epicardium and support a link between hypoxia inducible factors (HIFs) and the patterning of coronary vasculogenesis. To better understand the autocrine role of HIFs in the epicardium, we transduced adenovirus mediated expression of constitutively active HIF-1α (AdcaHIF1α) into the embryonic avian epicardium where the vascular precursors reside. We found that introducing caHIF1α into the epicardial mesothelium prevented EPDCs from proper migration into the myocardium. In vitro collagen gel assays and ex vivo organ culture data further confirmed that infection with AdcaHIF1α impaired the ability of EPDCs to invade. However, the proficiency of epicardial cells to undergo EMT was enhanced while the movement of EPDCs within the sub-epicardium and their differentiation into smooth muscle cells were not disrupted by caHIF1α. We also showed that the transcript level of Flt-1 (VEGFR1), which can act as a VEGF signaling inhibitor, increased several fold after introducing caHIF1α into epicardial cells. Blocking the activation of the VEGF pathway in epicardial cells recapitulated the inhibition of EPDC invasion. These results suggest that caHIF1α mediated up-regulation of Flt-1, which blocks the activation of the VEGF pathway, is responsible for the inhibition of EPDC myocardial migration. In conclusion, our studies demonstrate that HIF signaling potentially regulates the degree of epicardial EMT and the extent of EPDC migration into the myocardium, both of which are likely critical in patterning the coronary vasculature during early cardiac vasculogenesis. These signals could explain why the larger coronaries appear and remain on the epicardial surface.

Dataset Information

Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein- and fibroblast growth factor-signaling pathways.

Publications

Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein- and fibroblast growth factor-signaling pathways.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets