Cardiac fibroblast activation during myocardial infarction wound healing

Daseke, Michael J.; Tenkorang, Mavis A.A.; Chalise, Upendra; Lindsey, Merry L.

doi:10.1016/j.matbio.2020.03.010

Cited by 75 publications

(56 citation statements)

References 67 publications

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“…Often dedifferentiation is associated with heightened cellular proliferation (Daseke et al, 2020; Fu et al, 2018; Mouton et al, 2019b), and given MBNL1 overexpression inhibited cardiac fibroblast proliferation in MBNL1 Tg-Tcf21 iCre mice ( Fig. 3E-G ), we reasoned that loss of MBNL1 function would promote cardiac fibroblast proliferation.…”

Section: Resultsmentioning

confidence: 97%

“…Previous work has shown that cardiac fibroblasts undergo three state changes during the course of infarct repair including: a proliferative state in which resident fibroblasts expand (days 1-4); a myofibroblast state that forms provisional matrix and contracts the wound (days 4-14), and a matrifibrocyte state (days 14-21) in which osteogenic and cartilage genes are expressed to mature the ECM (Daseke et al, 2020; Fu et al, 2018; Mouton et al, 2019a). Here the transcriptional profile of cardiac fibroblasts was examined following myocardial infarction (MI) by RNAseq.…”

Section: Resultsmentioning

confidence: 99%

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Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

Bugg

Bretherton

Beach

et al. 2021

Preprint

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SUMMARYDynamic fibroblast state transitions are responsible for the heart’s fibrotic response to injury, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by the RNA binding protein Muscleblind Like 1 (MBNL1) has emerged as a potential driver of differentiated cell states. Here genetic lineage tracing of myofibroblasts in the injured heart demonstrated that gains in MBNL1 function corresponded to profibrotic fibroblast states. Similarly, in mice cardiac fibroblast specific MBNL1 overexpression induced a transcriptional myofibroblast profile in healthy cardiac fibroblasts that prevented the fibroproliferative phase of cardiac wound healing. By contrast loss of MBNL1 reverted cardiac fibroblasts to a pro-proliferative epicardial progenitor state that limited cardiac fibrosis following myocardial infarction. This progenitor state transition was associated with an MBNL1-dependent destabilization of the mesenchymal transition gene, Sox9. These findings suggest that MBNL1 regulation of the fibroblast transcriptome drives state transitions underlying cardiac fibrosis and repair.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

Bugg

Bretherton

Beach

et al. 2021

Preprint

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“…A structurally sufficient scar is necessary to reinforce the LV wall, but persistent fibrotic activity leads to chronic cardiac deterioration. 11,37 Therefore, it is desirable to properly tune the fibrotic response following MI such that a functional scar is able to form but is dampened before the activity of myofibroblasts becomes deleterious.…”

Section: Discussionmentioning

confidence: 99%

“…4 Insufficient ECM deposition can lead to LV rupture or aneurysm, while excessive ECM deposition leads to tissue stiffening, scar expansion, and arrhythmias. 11 Furthermore, replacement of contractile myocardium with a collagenous scar creates a local increase in mechanical strain at the BZ of surviving myocardium and scar tissue. To compensate for biomechanical alterations, connective tissue often expands beyond the original injury, creating a subsequent decline in tissue compliance and cardiac output.…”

Section: Introductionmentioning

confidence: 99%

Targeting 5-HT _2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction

et al. 2021

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Background: Myocardial infarction (MI) induces an intense injury response which ultimately generates a collagen-dominated scar. While required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process post-MI. Serotonin 2B receptor (5-HT 2B ) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI. Methods: We employed two pharmacologic antagonists to explore the effect of 5-HT 2B inhibition on outcomes post-MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible, 5-HT 2B ablation driven by Tcf21 MCM and Postn MCM were used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT 2B , respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype. Results: 5-HT 2B antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT 2B antagonism resulted in collagen fiber redistribution to thinner collagen fibers which were more anisotropic, enhancing left ventricular contractility, while fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT 2B from Tcf21 -lineage resident cardiac fibroblasts and saw similar improvements to the pharmacologic approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT 2B after onset of injury in Postn -lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in Dnajb4 expression and Src phosphorylation. Conclusions: Together, our findings illustrate that 5-HT 2B expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI.

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“…Furthermore, primary cultured cardiac fibroblasts from severe heart failure patients exhibited LPS-induced cytokine production with increased expression of CCL2, IFNγ, IL1β, IL6, IL8/CXCL8, and TNFα [ 103 ]. By 3 days after MI, cardiac fibroblasts transition towards proliferative and pro-angiogenic function before shifting toward a collagen and fibronectin depositing, profibrotic function 7 days after injury [ 104 ]. Due to the strong transcriptional similarity between dermal fibroblasts and cardiac fibroblasts [ 94 , 105 ], it is likely that dermal fibroblasts contribute to inflammation through mechanisms parallel to cardiac fibroblasts.…”

Section: Contribution Of Fibroblasts To Injury-induced Inflammatiomentioning

confidence: 99%

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

Cooper

Haas

Noonepalle

et al. 2021

IJMS

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Irregular inflammatory responses are a major contributor to tissue dysfunction and inefficient repair. Skin has proven to be a powerful model to study mechanisms that regulate inflammation. In particular, skin wound healing is dependent on a rapid, robust immune response and subsequent dampening of inflammatory signaling. While injury-induced inflammation has historically been attributed to keratinocytes and immune cells, a vast body of evidence supports the ability of non-immune cells to coordinate inflammation in numerous tissues and diseases. In this review, we concentrate on the active participation of tissue-resident adipocytes and fibroblasts in pro-inflammatory signaling after injury, and how altered cellular communication from these cells can contribute to irregular inflammation associated with aberrant wound healing. Furthering our understanding of how tissue-resident mesenchymal cells contribute to inflammation will likely reveal new targets that can be manipulated to regulate inflammation and repair.

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Cardiac fibroblast activation during myocardial infarction wound healing

Cited by 75 publications

References 67 publications

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

Targeting 5-HT _2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

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Cardiac fibroblast activation during myocardial infarction wound healing

Cited by 75 publications

References 67 publications

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

Targeting 5-HT 2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

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Targeting 5-HT _2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction