Immunomodulation of Myocardial Fibrosis

Sikking, Maurits A; Stroeks, Sophie L.V.M.; Marelli‐Berg, Federica M.; Heymans, Stéphane; Ludewig, Burkhard; Verdonschot, Job A.J.

doi:10.1016/j.jacbts.2023.03.015

Cited by 3 publications

(1 citation statement)

References 99 publications

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“…These myofibroblasts express highly contractile proteins, deposit matrix components, and secrete pro-inflammatory cytokines 1,2 , ultimately leading to cardiac fibrosis and dysfunction. The transition of cardiac fibroblasts to myofibroblasts can be triggered by extracellular stimuli such as growth factors and cytokines, communication with other cardiac cell types 4,5 , or intrinsic mechanisms within fibroblasts themselves, involving signaling, transcriptional and translational processes 2 .…”

Section: Introductionmentioning

confidence: 99%

Inactivation of PRMT1 inhibits cardiac fibrosis via transcriptional regulation and perturbation of FBL activity in fibroblast-to-myofibroblast transition

Qian,

Jackson-Weaver,

Shen

et al. 2024

Preprint

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Cardiac fibrosis is a recognized cause of morbidity and mortality, yet effective pharmacological therapy that directly targets the fibrotic process remains lacking. Here we surveyed a group of methyltransferases known as protein arginine methyltransferases (PRMT) and demonstrated that PRMT1, which is the most highly expressed PRMT in the heart, was upregulated in activated cardiac fibroblasts, or myofibroblasts, in failing hearts. Deleting Prmt1 specifically in myofibroblasts or treating systemically with the PRMT1 inhibitor MS023 blocked myofibroblast formation, leading to a significant reduction in cardiac fibrosis and improvement in cardiac function in both acute and chronic heart injury models that manifest pervasive cardiac fibrosis. PRMT1 promoted the transition of cardiac fibroblasts to myofibroblasts by regulating transcription and epigenetic status. Additionally, PRMT1 methylated a key nucleolar protein fibrillarin 1 (FBL) and regulated nucleoli morphology and function during fibroblast fate transition. We further demonstrated a previously unrecognized requirement for FBL in myofibroblasts formation, by regulating myofibroblast gene induction and contractile force generation.

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Section: Introductionmentioning

confidence: 99%

Inactivation of PRMT1 inhibits cardiac fibrosis via transcriptional regulation and perturbation of FBL activity in fibroblast-to-myofibroblast transition

Qian,

Jackson-Weaver,

Shen

et al. 2024

Preprint

View full text Add to dashboard Cite

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Nets in fibrosis: Bridging innate immunity and tissue remodeling

Ma,

Li,

et al. 2024

International Immunopharmacology

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Integrative Single-Cell Analysis of Cardiomyopathy Identifies Differences in Cell Stemness and Transcriptional Regulatory Networks among Fibroblast Subpopulations

Nie,

Zhao,

Liu

et al. 2024

Cardiology Research and Practice

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Background. Cardiomyopathy encompasses a broad spectrum of diseases affecting myocardial tissue, characterized clinically by abnormalities in cardiac structure, heart failure, and/or arrhythmias. Clinically heterogeneous, major types include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RM), ischemic cardiomyopathy (ICM), among which DCM is more prevalent, while ICM exhibits higher incidence and mortality rates. Myocardial injury during cardiomyopathy progression may lead to myocardial fibrosis. Failure to intervene early and inhibit the process of myocardial fibrosis may culminate in heart failure. Cardiac fibroblasts constitute crucial cellular components determining the extent and quality of myocardial fibrosis, with various subpopulations exerting diverse roles in cardiomyopathy progression. Despite this, understanding of the cellular plasticity and transcriptional regulatory networks of cardiac fibroblasts in cardiomyopathy remains limited. Therefore, in this study, we conducted comprehensive single-cell analysis of cardiac fibroblasts in cardiomyopathy to explore differences in cellular plasticity and transcriptional regulatory networks among fibroblast subpopulations, with the aim of providing as many useful references as possible for the diagnosis, prognosis, and treatment of cardiomyopathy. Materials and Methods. Cells with mitochondrial gene expression comprising >20% of total expressed genes were excluded. Differential expression genes (DEGs) and stemness genes within cardiac fibroblast subpopulations were subjected to Gene Ontology (GO) analysis of biological processes (BP) and AUCell analysis. Monocle software was employed to analyze the pseudo-temporal trajectory of cardiac fibroblasts in cardiomyopathy. Additionally, the Python package SCENIC was utilized to assess enrichment of transcription factors and activity of regulators within cardiac fibroblast subpopulations in cardiomyopathy. Results. Following batch effect correction, 179,927 cells were clustered into 32 clusters, designated as T_NK cells, endothelial cells, myeloid cells, fibroblasts, pericytes, SMCs, CMs, proliferating cells, EndoCs, and EPCs. Among them, 8148 fibroblasts were further subdivided into 4 subpopulations, namely C0 THBS4+ Fibroblasts, C1 LINC01133+ Fibroblasts, C2 FGF7+ Fibroblasts, and C3 AGT + Fibroblasts. Results from GO_BP and AUCell analyses suggest that C3 AGT + Fibroblasts may be associated with immune response activation, protein transport, and myocardial contractile function, correlating with disease progression in cardiomyopathy. Transcription factor enrichment analysis indicates that FOS is the most significant TF in C3 AGT + Fibroblasts, also associated with the M1 module, possibly implicated in protein hydrolysis, intracellular DNA replication, and cell proliferation. Moreover, correlation analysis of transcriptional regulatory activity between fibroblast subpopulations reveals a more pronounced heterogeneity within C3 AGT + Fibroblasts in cardiomyopathy. Conclusion. C3 AGT + Fibroblasts exhibit increased sensitivity towards adverse outcomes in cardiomyopathy, such as myocardial fibrosis and impaired cardiac contractile function, compared to other cardiac fibroblast subpopulations. The differential cellular plasticity and transcriptional regulatory activity between C3 AGT + Fibroblasts and other subgroups offer new perspectives for targeting fibroblast subpopulation activity to treat cardiomyopathy. Additionally, stemness genes EPAS1 and MYC, along with the regulator FOS, may play roles in modulating the biological processes of cardiac fibroblasts in cardiomyopathy.

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Immunomodulation of Myocardial Fibrosis

Cited by 3 publications

References 99 publications

Inactivation of PRMT1 inhibits cardiac fibrosis via transcriptional regulation and perturbation of FBL activity in fibroblast-to-myofibroblast transition

Inactivation of PRMT1 inhibits cardiac fibrosis via transcriptional regulation and perturbation of FBL activity in fibroblast-to-myofibroblast transition

Nets in fibrosis: Bridging innate immunity and tissue remodeling

Integrative Single-Cell Analysis of Cardiomyopathy Identifies Differences in Cell Stemness and Transcriptional Regulatory Networks among Fibroblast Subpopulations

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