Loss of Acta2 in cardiac fibroblasts does not prevent the myofibroblast differentiation or affect the cardiac repair after myocardial infarction
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ABSTRACT:
PROVIDER: PRJNA795160 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17468124_1.fastq.gz | Fastqsanger.gz | |||
| SRR17468124_2.fastq.gz | Fastqsanger.gz | |||
| SRR17468125_1.fastq.gz | Fastqsanger.gz | |||
| SRR17468125_2.fastq.gz | Fastqsanger.gz | |||
| SRR17468126_1.fastq.gz | Fastqsanger.gz |
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Project description:In response to myocardial infarction (MI), quiescent cardiac fibroblasts differentiate into myofibroblasts mediating tissue repair in the infarcted area. One of the most widely accepted markers of myofibroblast differentiation is the expression of Acta2 which encodes smooth muscle alpha-actin (SMαA) that is assembled into stress fibers. However, the requirement of Acta2/ SMαA in the myofibroblast differentiation of cardiac fibroblasts and its role in post-MI cardiac repair remained largely unknown. To answer these questions, we generated a tamoxifen-inducible cardiac fibroblast-specific Acta2 knockout mouse line. Surprisingly, mice that lacked Acta2 in cardiac fibroblasts had a normal survival rate after MI. Moreover, Acta2 deletion did not affect the function or overall histology of infarcted hearts. No difference was detected in the proliferation, migration, or contractility between WT and Acta2-null cardiac myofibroblasts. It was identified that Acta2-null cardiac myofibroblasts had a normal total filamentous actin level and total actin level. Acta2 deletion caused a significant compensatory increase in the transcription level of non- Acta2 actin isoforms, especially Actg2 and Acta1, 2 other muscle actin isoforms. Moreover, in myofibroblasts the transcription levels of cytoplasmic actin isoforms were significantly higher than those of muscle actin isoforms. In addition, we found that myocardin-related transcription factor-A is critical for myofibroblast differentiation but is not required for the compensatory effects of non-Acta2 isoforms. In conclusion, the deletion of Acta2 does not prevent the myofibroblast differentiation of cardiac fibroblasts or affect the post-MI cardiac repair, and the increased expression and stress fiber formation of non-SMαA actin isoforms and the functional redundancy between actin isoforms are able to compensate for the loss of Acta2 in cardiac myofibroblasts.
2022-01-10 | GSE193163 | GEO
Project description:In response to myocardial infarction (MI), quiescent cardiac fibroblasts differentiate into myofibroblasts mediating tissue repair. One of the most widely accepted markers of myofibroblast differentiation is the expression of Acta2 which encodes smooth muscle alpha-actin (SMαA) that is assembled into stress fibers. However, the requirement of Acta2/SMαA in the myofibroblast differentiation of cardiac fibroblasts and its role in post-MI cardiac repair remained unknown. To answer these questions, we generated a tamoxifen-inducible cardiac fibroblast-specific Acta2 knockout mouse line. Surprisingly, mice that lacked Acta2 in cardiac fibroblasts had a normal post-MI survival rate. Moreover, Acta2 deletion did not affect the function or histology of infarcted hearts. No difference was detected in the proliferation, migration, or contractility between WT and Acta2-null cardiac myofibroblasts. Acta2-null cardiac myofibroblasts had a normal total filamentous actin level and total actin level. Acta2 deletion caused a significant compensatory increase in the transcription level of non-Acta2 actin isoforms, especially Actg2 and Acta1. Moreover, in myofibroblasts, the transcription levels of cytoplasmic actin isoforms were significantly higher than those of muscle actin isoforms. In addition, we found that myocardin-related transcription factor-A is critical for myofibroblast differentiation but is not required for the compensatory effects of non-Acta2 isoforms. In conclusion, the Acta2 deletion does not prevent the myofibroblast differentiation of cardiac fibroblasts or affect the post-MI cardiac repair, and the increased expression and stress fiber formation of non-SMαA actin isoforms and the functional redundancy between actin isoforms are able to compensate for the loss of Acta2 in cardiac myofibroblasts.
| S-EPMC10478266 | biostudies-literature
Project description:Differentiation of cardiac fibroblasts (CFs) to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting the myofibroblast gene program. Here, we investigated the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast formation and persistence in cardiac fibrosis. Inactivation of ACLY prevented, and importantly reversed, myofibroblasts towards quiescence. Genetic deletion of Acly in activated myofibroblasts prevented fibrosis and preserved cardiac function in murine pressure-overload. TGFβ stimulation enhanced ACLY nuclear localization and increased H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of dominant-negative ACLY mutant prevented myofibroblast formation and H3K27ac. Our data indicate nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide novel clinical rational to prevent and reverse pathological fibrosis. CUT&RUN Sequencing for H3K27ac on the role of ACLY in myofibroblast differentiaton.
2024-05-16 | GSE232010 | GEO
Project description:Cardiac pericytes contribute to myofibroblast expansion and vascular maturation following myocardial infarction
| PRJNA922047 | ENA
Project description:Objectives: To investigate the role of ALKBH5 in fibroblasts during post-myocardial infarction (MI) repair. Background: N6-methyladenosine (m6A) mRNA modification has been shown to play an important role in cardiovascular diseases. The RNA demethylase, AlkB homolog 5 (ALKBH5), is an m6A "eraser" that is responsible for decreased m6A methylation. However, its role in cardiac fibroblasts during the post-MI healing process remains elusive. Methods: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Results: Dramatic alterations in ALKBH5 expression were observed during the early stage post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and improved cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss led to impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts in a HIF-1α-dependent transcriptional manner. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Conclusions: Fibroblast ALKBH5 positively regulates post-MI healing via post-transcriptional modification and stabilization of ErbB4 mRNA in an m6A-dependent manner. Targeting ALKBH5/ERBB4 may be a potential therapeutic option for post-MI cardiac rupture.
2023-10-01 | GSE226415 | GEO
Project description:We show that activity of the RNA binding protein HuR is necessary for myofibroblast activation. This data set identifies directly bound HuR target genes in quiescent cardiac fibroblasts and active myofibroblasts.
2022-11-01 | GSE193931 | GEO
Project description:Transcription factor 21 (TCF21) is a basic helix-loop-helix protein required for developmental specification of cardiac fibroblasts from epicardial progenitor cells that normally surround and invade the heart. In the adult heart, TCF21 is expressed in tissue-resident fibroblasts but is downregulated in response to injury or stimuli leading to myofibroblast differentiation. These findings led to the hypothesis that Tcf21 could be a regulator of fibroblast cell fate in the adult mammalian heart and contribute to cardiac fibrosis. Here, single-cell RNA-sequencing was used to study the effect of loss of Tcf21 in cardiac fibroblasts in adult mouse hearts at baseline and after an ischemic cardiac injury (myocardial infarction).
2024-12-03 | GSE261150 | GEO
Project description:Transcription factor 21 (TCF21) is a basic helix-loop-helix protein required for developmental specification of cardiac fibroblasts from epicardial progenitor cells that normally surround and invade the heart. In the adult heart, TCF21 is expressed in tissue resident fibroblasts but is downregulated in response to injury or stimuli leading to myofibroblast differentiation. These findings led to the hypothesis that Tcf21 could be a regulator of fibroblast cell-fate in the adult mammalian heart and contribute to cardiac fibrosis. Here, chromatin immunoprecipitation followed by sequencing was used to identify TCF21 genome occupancy in adult cardiac fibroblasts.
2024-12-03 | GSE276785 | GEO
Project description:Transcription factor 21 (TCF21) is a basic helix-loop-helix protein required for developmental specification of cardiac fibroblasts from epicardial progenitor cells that normally surround and invade the heart. In the adult heart, TCF21 is expressed in tissue resident fibroblasts but is downregulated in response to injury or stimuli leading to myofibroblast differentiation. These findings led to the hypothesis that Tcf21 could be a regulator of fibroblast cell-fate in the adult mammalian heart and contribute to cardiac fibrosis. Here, bulk RNA sequencing was used to determine the effect of loss of TCF21 and enforced TCF21 expression in adult cardiac fibroblasts.
2024-12-03 | GSE261166 | GEO
Project description:Repair of the infarcted heart requires TGFβ-Smad3 signaling in cardiac myofibroblasts. However, TGF-β-driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7 may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in β-SMA+ infarct myofibroblasts, but not in β-SMA-/PDGFRα+ fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure-related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 actions on TGF-β cascades involved de-activation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with Erbb2 in a TGF-independent manner and restrained Erbb1/Erbb2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-independent fibrogenic actions of Erbb2.
2021-11-11 | GSE185767 | GEO