scholarly journals A specialized population of Periostin-expressing cardiac fibroblasts contributes to postnatal cardiomyocyte maturation and innervation

2020 ◽  
Vol 117 (35) ◽  
pp. 21469-21479
Author(s):  
Luis Hortells ◽  
Iñigo Valiente-Alandi ◽  
Zachary M. Thomas ◽  
Emma J. Agnew ◽  
Dan J. Schnell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Development ◽  
Neuronal Development ◽  
Cardiac Fibroblasts ◽  
Postnatal Period ◽  
Hypertrophic Growth ◽  
Cycle Arrest ◽  
Reporter Mice ◽  
Differentially Express Genes ◽  
And Function

During the postnatal period in mammals, the cardiac muscle transitions from hyperplasic to hypertrophic growth, the extracellular matrix (ECM) undergoes remodeling, and the heart loses regenerative capacity. While ECM maturation and crosstalk between cardiac fibroblasts (CFs) and cardiomyocytes (CMs) have been implicated in neonatal heart development, not much is known about specialized fibroblast heterogeneity and function in the early postnatal period. In order to better understand CF functions in heart maturation and postnatal cardiomyocyte cell-cycle arrest, we have performed gene expression profiling and ablation of postnatal CF populations. Fibroblast lineages expressing Tcf21 or Periostin were traced in transgenic GFP reporter mice, and their biological functions and transitions during the postnatal period were examined in sorted cells using RNA sequencing. Highly proliferative Periostin (Postn)+ lineage CFs were found from postnatal day 1 (P1) to P11 but were not detected at P30, due to a repression ofPostngene expression. This population was less abundant and transcriptionally different from Tcf21+ resident CFs. The specialized Postn+ population preferentially expresses genes related to cell proliferation and neuronal development, while Tcf21+ CFs differentially express genes related to ECM maturation at P7 and immune crosstalk at P30. Ablation of the Postn+ CFs from P0 to P6 led to altered cardiac sympathetic nerve patterning and a reduction in binucleation and hypertrophic growth with increased fetal troponin (TroponinI1) expression in CM. Thus, postnatal CFs are heterogeneous and include a transient proliferative Postn+ population required for cardiac nerve development and cardiomyocyte maturation soon after birth.

Abstract 255: A Fibroblast Population Shares A Developmental Origin With Cardiovascular Lineages

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Sara Ranjbarvaziri ◽  
Shah Ali ◽  
Mahmood Talkhabi ◽  
Peng Zhao ◽  
Young-Jae Nam ◽  
...  
Keyword(s):  
Heart Development ◽  
Cardiac Fibroblasts ◽  
Immunohistochemical Analysis ◽  
Cell Types ◽  
Mouse Heart ◽  
Developmental Potential ◽  
Reporter Mice ◽  
Significant Difference ◽  
Definition Of

Rationale: The traditional definition of “cardiovascular” lineages describes the eponymous cell types - cardiomyoctes, endothelial cells, and smooth muscle cells - that arise from a common mesodermal progenitor cell during heart development. Fibroblasts are an abundant mesenchymal population in the mammalian heart which may have multiple, discrete developmental origins. Mesp1 represents the earliest marker of cardiovascular progenitors, contributing to the majority of cardiac lineages. To date no link between Mesp1 and fibroblast generation has been reported. Objective: We hypothesized progenitor cells expressing Mesp1 can also give rise to cardiac fibroblasts during heart development. Methods and Results: We generated Mesp1cre/+;R26RmTmG reporter mice where Cre-mediated recombination results in GFP activation in all Mesp1 expressing cells and their progeny. To explore their developmental potential, we isolated GFP+ cells from E7.5 Mesp1cre/+;R26RmTmG mouse. In vitro culture and transplantation studies into SCID mouse kidney capsule as wells as chick embryos showed fibroblastic adoption. Results showed that at E9.5 Mesp1+ and Mesp1- progenitors contributed to the proepicardium organ and later at E11.5 they formed epicardium. Analysis of adult hearts demonstrated that the majority of cardiac fibroblasts are derived from Mesp1 expressing cells. Immunohistochemical analysis of heart sections demonstrated expression of fibroblast markers (including DDR2, PDGFRα and Col1) in cells derived from both Mesp1+ and Mesp1- progenitors. Additionally, we investigated whether the two distinct fibroblast populations have different potency towards reprogramming to cardiomyocytes. Results showed no significant difference between Mesp1 and non-Mesp1 isolated fibroblasts to convert to cardiomyocyte fate. Conclusions: Our data demonstrates that cardiovascular progenitors expressing Mesp1 contribute to the proepicardium. These cells, as cardiovascular progenitors, also give rise to the highest portion of cardiac fibroblasts in the mouse heart.

scholarly journals Dioxin Disrupts Dynamic DNA Methylation Patterns in Genes That Govern Cardiomyocyte Maturation

2020 ◽  
Vol 178 (2) ◽  
pp. 325-337
Author(s):  
Matthew de Gannes ◽  
Chia-I Ko ◽  
Xiang Zhang ◽  
Jacek Biesiada ◽  
Liang Niu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Heart Development ◽  
Expression Patterns ◽  
Embryonic Stem Cell Line ◽  
Molecular Networks ◽  
Unknown Etiology ◽  
Postnatal Maturation ◽  
Complex Interactions ◽  
And Function

Abstract Congenital heart disease (CHD), the leading birth defect worldwide, has a largely unknown etiology, likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory has shown that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. To test the hypothesis that the disruption caused by TCDD in the heart results from changes in DNA methylation and gene expression patterns of cardiomyocytes, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under control of the cardiomyocyte-specific Nkx2-5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte-specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 111 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue toward the elucidation of the complex interactions between genetic and epigenetic mechanisms after developmental TCDD exposure that may contribute to CHD.

scholarly journals Cardiomyopathy in Irx4-Deficient Mice Is Preceded by Abnormal Ventricular Gene Expression

2001 ◽  
Vol 21 (5) ◽  
pp. 1730-1736 ◽  
Author(s):  
Benoit G. Bruneau ◽  
Zheng-Zheng Bao ◽  
Diane Fatkin ◽  
Jose Xavier-Neto ◽  
Dimitrios Georgakopoulos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Heart Development ◽  
Contractile Function ◽  
Specific Gene ◽  
Postnatal Life ◽  
Helix Loop Helix ◽  
And Function ◽  
Expression Program ◽  
Deficient Mice

ABSTRACT To define the role of Irx4, a member of the Iroquoisfamily of homeobox transcription factors in mammalian heart development and function, we disrupted the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designatedIrx4 Δex2/Δex2) was normal during embryogenesis and in early postnatal life. AdultIrx4 Δex2/Δex2 mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy,Irx4 Δex2/Δex2 hearts had abnormal ventricular gene expression: Irx4-deficient embryos exhibited reduced ventricular expression of the basic helix-loop-helix transcription factor eHand (Hand1), increasedIrx2 expression, and ventricular induction of an atrial chamber-specific transgene. In neonatal hearts, ventricular expression of atrial natriuretic factor and α-skeletal actin was markedly increased. Several weeks subsequent to these changes in embryonic and neonatal gene expression, increased expression of hypertrophic markers BNP and β-myosin heavy chain accompanied adult-onset cardiac hypertrophy. Cardiac expression of Irx1, Irx2, and Irx5 may partially compensate for loss of Irx4 function. We conclude that Irx4 is not sufficient for ventricular chamber formation but is required for the establishment of some components of a ventricle-specific gene expression program. In the absence of genes under the control of Irx4, ventricular function deteriorates and cardiomyopathy ensues.

Fractal and Image Analysis of Morphological Changes in the Actin Cytoskeleton of Neonatal Cardiac Fibroblasts in Response to Mechanical Stretch

2007 ◽  
Vol 13 (2) ◽  
pp. 133-143 ◽  
Author(s):  
John W. Fuseler ◽  
Clarke F. Millette ◽  
Jeffery M. Davis ◽  
Wayne Carver
Keyword(s):  
Gene Expression ◽  
Image Analysis ◽  
Actin Cytoskeleton ◽  
Mechanical Stress ◽  
Heart Development ◽  
Morphological Changes ◽  
Cardiac Fibroblasts ◽  
Mechanical Stretch ◽  
Cell Types ◽  
Actin Organization

Cardiac fibroblasts are the most numerous cells in the heart and are critical in the formation and normal functioning of the organ. Cardiac fibroblasts are firmly attached to and surrounded by extracellular matrix (ECM). Mechanical forces transmitted through interaction with the ECM can result in changes of overall cellular shape, cytoskeletal organization, proliferation, and gene expression of cardiac fibroblasts. These responses may be different in the normally functioning heart, when compared with various pathological conditions, including inflammation or hypertrophy. It is apparent that cellular phenotype and physiology, in turn, are affected by multiple signal transduction pathways modulated directly by the state of polymerization of the actin cytoskeleton. Morphological changes in actin organization resulting from response to adverse conditions in fibroblasts and other cell types are basically descriptive. Some studies have approached quantifying changes in actin cytoskeletal morphology, but these have involved complex and difficult procedures. In this study, we apply image analysis and non-Euclidian geometrical fractal analysis to quantify and describe changes induced in the actin cytoskeleton of cardiac fibroblasts responding to mechanical stress. Characterization of these rapid responses of fibroblasts to mechanical stress may provide insight into the regulation of fibroblasts behavior and gene expression during heart development and disease.

scholarly journals Deregulated Cardiac Specific MicroRNAs in Postnatal Heart Growth

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Pujiao Yu ◽  
Hongbao Wang ◽  
Yuan Xie ◽  
Jinzhe Zhou ◽  
Jianhua Yao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Development ◽  
Growth Period ◽  
Heart Tissue ◽  
Postnatal Period ◽  
Multiple Systems ◽  
Functional Annotations ◽  
Qrt Pcr ◽  
Kegg Analysis

The heart is recognized as an organ that is terminally differentiated by adulthood. However, during the process of human development, the heart is the first organ with function in the embryo and grows rapidly during the postnatal period. MicroRNAs (miRNAs, miRs), as regulators of gene expression, play important roles during the development of multiple systems. However, the role of miRNAs in postnatal heart growth is still unclear. In this study, by using qRT-PCR, we compared the expression of seven cardiac- or muscle-specific miRNAs that may be related to heart development in heart tissue from mice at postnatal days 0, 3, 8, and 14. Four miRNAs—miR-1a-3p, miR-133b-3p, miR-208b-3p, and miR-206-3p—were significantly decreased while miR-208a-3p was upregulated during the postnatal heart growth period. Based on these results, GeneSpring GX was used to predict potential downstream targets by performing a 3-way comparison of predictions from the miRWalk, PITA, and microRNAorg databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to identify potential functional annotations and signaling pathways related to postnatal heart growth. This study describes expression changes of cardiac- and muscle-specific miRNAs during postnatal heart growth and may provide new therapeutic targets for cardiovascular diseases.

Abstract 66: Unique Cardiac Fibroblast Expression Profiles in Pathological and Physiological Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Janet K Lighthouse ◽  
Lissette S Velasquez ◽  
Eric M Small
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pressure Overload ◽  
Gene Expression Signature ◽  
Hypertrophic Growth ◽  
Physiological Hypertrophy

The heart undergoes hypertrophic growth in response to both physiological and pathological stimuli. Pathological hypertrophy results from various humoral, mechanical, or ischemic insults, and often leads to cardiac fibrosis, diminished contractility, and heart failure. In contrast, physiological hypertrophy is an adaptive response to the excessive demands of exercise or pregnancy and does not lead to fibrosis. We hypothesized that cardiac fibroblasts, the main cellular source of extracellular matrix in the heart, exhibit distinct expression profiles in physiological or pathological remodeling that influence the divergent fibrotic response. To investigate these differences, we obtained the expression profile of cardiac fibroblasts isolated from mice subjected to swim training, pressure-overload induced cardiac remodeling, or myocardial infarction by RNA-sequencing. Although we observed cardiac growth in all conditions, pressure-overload induced hypertrophy and myocardial infarction induced the predicted fibrotic gene expression signature, which was absent in physiological hypertrophy. Utilizing these validated datasets, we identified novel genes and molecular pathways that are differentially expressed in physiological and pathological hypertrophic remodeling and will correlate transcriptional programs with altered gene profiles. Fibroblast gene expression profiles in pathological and physiological are expected to lead to diagnostic or prognostic markers of fibrotic remodeling as well as genes that may serve as novel therapeutic strategies to prevent or reverse cardiac fibrosis.

scholarly journals Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

Biology Open ◽  
2017 ◽  
Vol 7 (1) ◽  
pp. bio029512 ◽  
Author(s):  
Xin Sun ◽  
Swetansu K. Hota ◽  
Yu-Qing Zhou ◽  
Stefanie Novak ◽  
Dario Miguel-Perez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Heart Development ◽  
Chromatin Remodeling Complex ◽  
And Function

scholarly journals Cardiac enriched BAF chromatin remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

2017 ◽  
Author(s):  
Xin Sun ◽  
Swetansu K. Hota ◽  
Yu-Qing Zhou ◽  
Stefanie Novak ◽  
Dario Miguel-Perez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Heart Development ◽  
Gene Networks ◽  
Contractile Function ◽  
Conditional Deletion ◽  
Genes Encoding ◽  
Organ Specific ◽  
Chromatin Remodeling Complexes ◽  
And Function

AbstractHow gene networks controlling organ-specific properties are modulated by chromatin remodeling complexes is not well understood. Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex. Its role throughout heart development is not fully understood. We show that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes results in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen we identify MYOCD as a BAF60c interacting factor; we show that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

CARP Plays a Key Role in Cellular Growth Under Hypertrophic Stimuli in Neonatal Rat Ventricular Myocytes

2013 ◽  
Vol 9 ◽  
Author(s):  
Tara A Shrout
Keyword(s):  
Gene Expression ◽  
Ventricular Myocytes ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Transcriptional Level ◽  
Dual Nature ◽  
Hypertrophic Growth ◽  
Rat Ventricular Myocytes ◽  
Neonatal Rat Ventricular Myocytes ◽  
Over Time

Cardiac hypertrophy is a growth process that occurs in response to stress stimuli or injury, and leads to the induction of several pathways to alter gene expression. Under hypertrophic stimuli, sarcomeric structure is disrupted, both as a consequence of gene expression and local changes in sarcomeric proteins. Cardiac-restricted ankyrin repeat protein (CARP) is one such protein that function both in cardiac sarcomeres and at the transcriptional level. We postulate that due to this dual nature, CARP plays a key role in maintaining the cardiac sarcomere. GATA4 is another protein detected in cardiomyocytes as important in hypertrophy, as it is activated by hypertrophic stimuli, and directly binds to DNA to alter gene expression. Results of GATA4 activation over time were inconclusive; however, the role of CARP in mediating hypertrophic growth in cardiomyocytes was clearly demonstrated. In this study, Neonatal Rat Ventricular Myocytes were used as a model to detect changes over time in CARP and GATA4 under hypertrophic stimulation by phenylephrine and high serum media. Results were detected by analysis of immunoblotting. The specific role that CARP plays in mediating cellular growth under hypertrophic stimuli was studied through immunofluorescence, which demonstrated that cardiomyocyte growth with hypertrophic stimulation was significantly blunted when NRVMs were co-treated with CARP siRNA. These data suggest that CARP plays an important role in the hypertrophic response in cardiomyocytes.

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