Cardiac fibroblast sub-types in vitro reflect pathological cardiac remodeling in vivo

Herum, Kate M.; Weng, Guangzheng; Kahnert, Konstantin; Waikel, Rebekah L.; Milburn, Gregory; Conger, Autumn; Anaya, Paul; Campbell, Kenneth S.; Lundby, Alicia; Won, Kyoung Jae; Brakebusch, Cord

doi:10.1016/j.mbplus.2022.100113

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…However, the functional roles of these novel cell states and how they might interact during disease pathogenesis remains to be defined. Among stromal cell types, fibroblasts are of particular interest given their role in tissue fibrosis, arrhythmias, and heart failure 19,33,34 . Little is known regarding the mechanisms and signaling events that orchestrate the specification of pathogenic fibroblasts in the context of human MI and HF.…”

Section: Discussionmentioning

confidence: 99%

“…However, the precise fibroblast populations that are responsible for fibrosis in the human heart and mechanisms that orchestrate their emergence and maturation are unknown. Furthermore, it is not clear which of the many available pre-clinical animal and in vitro experimental models [14][15][16][17][18][19] best recapitulate human cardiac fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

Lavine¹,

Amrute

Luo

et al. 2023

Preprint

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Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored and there are currently no therapeutics to target fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 38 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. Pro-fibrotic fibroblasts were transcriptionally similar to cancer associated fibroblasts and expressed high levels of collagens and periostin (POSTN), thymocyte differentiation antigen 1 (THY-1), and endothelin receptor A (EDNRA) predicted to be driven by a RUNX1 gene regulatory network. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1β) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. This concept was validated through in silico transcription factor perturbation and in vivo inhibition of IL-1β signaling in fibroblasts where we observed reduced pro-fibrotic fibroblasts, preferential differentiation of fibroblasts towards myofibroblasts, and reduced cardiac fibrosis. Herein, we show a subset of macrophages signal to fibroblasts via IL-1β and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and restore organ function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

Lavine¹,

Amrute

Luo

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…However, the functional roles of these novel cell states and how they might interact during disease pathogenesis remains to be defined. Among stromal cell types, fibroblasts are of particular interest given their role in tissue fibrosis, arrhythmias, and heart failure 16, 29, 30 . Little is known regarding the mechanisms and signaling mechanisms that orchestrate the specification of pathogenic fibroblasts in the context of human MI and HF.…”

Section: Discussionmentioning

confidence: 99%

“…The precise fibroblast populations that are responsible for fibrosis in the human heart and mechanisms that orchestrate their emergence and maturation are unknown. Furthermore, it is not clear which of the many available pre-clinical animal and in vitro experimental models [11][12][13][14][15][16] best recapitulate human cardiac fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure

Amrute

Luo

Penna

et al. 2022

Preprint

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Cardiac fibrosis is causally linked to heart failure pathogenesis and adverse clinical outcomes. However, the precise fibroblast populations that drive fibrosis in the human heart and the mechanisms that govern their emergence remain incompletely defined. Here, we performed Cellular Indexing of Transcriptomes and Epitomes by sequencing (CITE-seq) in 22 explanted human hearts from healthy donors, acute myocardial infarction (MI), and chronic ischemic and non-ischemic cardiomyopathy patients. We identified a fibroblast trajectory marked by fibroblast activator protein (FAP) and periostin (POSTN) expression that was independent of myofibroblasts, peaked early after MI, remained elevated in chronic heart failure, and displayed a transcriptional signature consistent with fibrotic activity. We assessed the applicability of cardiac fibrosis models and demonstrated that mouse MI, angiotensin II/phenylephrine infusion, and pressure overload models were superior compared to cultured human heart and dermal fibroblasts in recapitulating cardiac fibroblast diversity including pathogenic cell states. Ligand-receptor analysis and spatial transcriptomics predicted interactions between macrophages, T cells, and fibroblasts within spatially defined niches. CCR2+monocyte and macrophage states were the dominant source of ligands targeting fibroblasts. Inhibition of IL-1β signaling to cardiac fibroblasts was sufficient to suppress fibrosis, emergence, and maturation of FAP+POSTN+fibroblasts. Herein, we identify a human fibroblast trajectory marked by FAP and POSTN expression that is associated with cardiac fibrosis and identify macrophage-fibroblast crosstalk mediated by IL-1β signaling as a key regulator of pathologic fibroblast differentiation and fibrosis.

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“…Although we did not see changes in total collagen in hearts in vivo, Adamtsl3 inactivation resulted in altered ECM quality in the myocardium, with increased levels of insoluble collagen, that we speculate could be attributed to enhanced expression of Lox . Recent evidence suggest that the failing heart contains distinctive populations of activated CFBs, which hold varying characteristics, such as highly contractile, or highly collagen-producing 4 , 33 . We speculate that ADAMTSL3 may affect differentiation of specific myofibroblast populations that remodel the myocardium in ways other than mere collagen production.…”

Section: Discussionmentioning

confidence: 99%

ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure overload

et al. 2022

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Heart failure is a major cause of morbidity and mortality worldwide, and can result from pressure overload, where cardiac remodelling is characterized by cardiomyocyte hypertrophy and death, fibrosis, and inflammation. In failing hearts, transforming growth factor (TGF)β drives cardiac fibroblast (CFB) to myofibroblast differentiation causing excessive extracellular matrix production and cardiac remodelling. New strategies to target pathological TGFβ signalling in heart failure are needed. Here we show that the secreted glycoprotein ADAMTSL3 regulates TGFβ in the heart. We found that Adamtsl3 knock-out mice develop exacerbated cardiac dysfunction and dilatation with increased mortality, and hearts show increased TGFβ activity and CFB activation after pressure overload by aortic banding. Further, ADAMTSL3 overexpression in cultured CFBs inhibits TGFβ signalling, myofibroblast differentiation and collagen synthesis, suggesting a cardioprotective role for ADAMTSL3 by regulating TGFβ activity and CFB phenotype. These results warrant future investigation of the potential beneficial effects of ADAMTSL3 in heart failure.

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Cardiac fibroblast sub-types in vitro reflect pathological cardiac remodeling in vivo

Cited by 6 publications

References 26 publications

Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure

ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure overload

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