Targeting immune–fibroblast cell communication in heart failure

In the paper

“However, these studies rely on nuclear RNA information and lack cellular transcriptomic, epigenetic and proteomic profiling information necessary to obtain a granular picture of the precise immune and fibroblast populations that emerge in the failing human heart and collaborate to drive cardiac fibrosis.”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Tucker, N. R. et al. Transcriptional and cellular diversity of the human heart. Circulation 142, 466–482 (2020). source
• Partly supported

  The Methods describe single-nucleus RNA sequencing, supporting the claim that this study relies on nuclear RNA rather than integrated cellular transcriptomic, epigenetic and proteomic profiling. But the ‘Changes in cell sub-populations’ and ‘Activated fibroblasts in DCM and HCM’ sections identify macrophage sub-populations and a disease-associated activated fibroblast population. The paper therefore does not support the implication that its approach cannot provide a granular picture of those populations, or establish that the additional profiling is necessary to do so. (LLM, conf=0.86)

  cites [19] Chaffin, M. et al. Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy. Nature https://doi.org/10.1038/S41586-022-04817-8 (2022). sourceExperimental — accuracy not yet measured
• Disputed

  The Results section (‘snRNA-seq and scRNA-seq reveal the cellular landscape of the human heart’; page unavailable) says this study sequenced both nuclei and whole cells, contrary to the claim that it relied only on nuclear RNA and lacked cellular transcriptomic profiling. The Discussion (page unavailable) also describes distinct fibroblast populations in healthy and failing hearts. The paper does not establish the claim about missing epigenetic or proteomic profiling. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  cites [20] Koenig, A. L. et al. Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure. Nat. Cardiovasc. Res. 1, 263–280 (2022). sourceExperimental — accuracy not yet measured
• Disputed

  The Main section (page unavailable) says this study combines snRNA-seq with scRNA-seq to enrich immune-cell populations; the Discussion likewise describes combined single-cell and single-nucleus data. Thus, contrary to the claim, this source does not rely only on nuclear RNA or lack cellular transcriptomic profiling. It studies the healthy adult heart rather than profiling immune and fibroblast populations emerging in heart failure. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [21] Litviňuková, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Methods describe a study based on single-nucleus RNA sequencing, and the Discussion calls for future epigenomic and proteomic work. But the Results already distinguish fibroblast states and 14 myeloid subclusters and discuss fibroblast–macrophage interactions in fibrosis. The source therefore supports the missing-modality point, not the implication that its nuclear-RNA data cannot provide a granular picture of those populations. (LLM, conf=0.86)

  cites [22] Reichart, D. et al. Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies. Science 377, eabo1984 (2022). sourceExperimental — accuracy not yet measured

In the paper

“there are at present no approved treatments that directly target cardiac fibrosis3,4.”

What the sources say

• ?Could not verify

  The Abstract says trials of anti-fibrotic therapeutics have shown at most modest effects and that these interventions aim to limit progression rather than remodel established fibrosis. It does not state whether any treatment that directly targets cardiac fibrosis has been approved; searches for approved anti-fibrotic treatments found no passage resolving that point. (LLM, conf=0.72)

  cites [3] Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022). sourceExperimental — accuracy not yet measured
• Supported

  The Abstract states that no therapies are known to directly target excessive fibrosis. In the paper’s discussion of cardiac fibrosis, this supports the claim that no approved treatment directly targets it. (LLM, conf=0.92)

  cites [4] Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019). source

In the paper

“To validate our findings, we used spatial transcriptomics data from human MI25 at days 2, 11, 62 and 153 post-MI and found FAP expression was most prominent acutely after MI and diminished at later time points (Fig. 2e, bottom).”

What the sources say

• Supported

  The citation identifies the human MI spatial-transcriptomics dataset used by the citing authors. The source’s “Multi-omic map of myocardial infarction” section describes spatial transcriptomics of human heart tissue collected at different stages after MI. The FAP expression pattern is presented as the citing authors’ own finding, not a finding attributed to this source. (LLM, conf=0.88)

  cites [25] Kuppe, C. et al. Spatial multi-omic map of human myocardial infarction. Nature https://doi.org/10.1038/s41586-022-05060-x (2022). source

In the paper

“In support of this concept, a large clinical trial targeting the IL-1β pathway with the neutralizing antibody canakinumab led to a reduction in cardiac events31.”

What the sources say

• Supported

  The Methods describe a randomized trial of 10,061 patients using canakinumab, a monoclonal antibody targeting interleukin-1β. The Conclusions report significantly fewer recurrent cardiovascular events with the 150-mg dose than with placebo in patients with previous myocardial infarction and elevated C-reactive protein. (LLM, conf=0.94)

  cites [31] Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017). source

In the paper

“We chose to focus on IL-1β signalling given the availability and clinical efficacy of the anti-IL-1β monoclonal antibody (mAb) canakinumab31.”

What the sources say

• Supported

  The Methods identify canakinumab as a monoclonal antibody targeting IL-1β. The Conclusions report clinical efficacy: the 150-mg dose significantly lowered recurrent cardiovascular events versus placebo in patients with prior myocardial infarction and elevated C-reactive protein. (LLM, conf=0.93)

  cites [31] Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017). source

In the paper

“and resemble POSTN-expressing matrifibrocytes7.”

What the sources say

• Partly supported

  The Results section on cardiac fibroblast proliferation following MI reports Postn expression in activated cardiac fibroblasts, and the Discussion describes matrifibrocytes as a later fibroblast state in the scar (pages not provided). Our copy does not identify FAP-positive fibroblasts or compare them with matrifibrocytes, so the claimed resemblance is not established. (LLM, conf=0.79)

  cites [7] Fu, X. et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J. Clin. Invest. 128, 2127–2143 (2018). sourceExperimental — accuracy not yet measured

In the paper

“By contrast, cultured human primary cardiac and dermal fibroblasts and immortalized cardiac fibroblasts were relatively poor models of human cardiac fibroblast diversity under resting or stimulated (TGFβ (refs. 19,39,40), IL-1β (ref. 41)) conditions.”

What the sources say

• Partly supported

  The Cardiac fibrosis assay and Methods sections (pages unavailable) describe stimulating cultured human cardiac fibroblasts with TGFβ1, supporting the TGFβ condition cited in the sentence. The paper does not compare cultured cardiac, dermal, and immortalized fibroblasts as models of human cardiac fibroblast diversity. Its Discussion instead says it is not yet known how well the cultured-cell transition reflects the trajectory inferred from single-nucleus data. (LLM, conf=0.82)

  cites [19] Chaffin, M. et al. Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy. Nature https://doi.org/10.1038/S41586-022-04817-8 (2022). sourceExperimental — accuracy not yet measured
• Supported

  The citation is attached to TGFβ as a stimulation condition, rather than to the citing authors’ assessment of model fidelity. The Methods (p. 11) describe treating cultured heart and skin fibroblasts with TGFβ, and the Results (p. 3) report responses of TGFβ-stimulated primary cardiac fibroblasts. (LLM, conf=0.89)

  cites [39] Khalil, H. et al. Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis. J. Clin. Invest. 127, 3770–3783 (2017). source
• Partly supported

  The Results section, “BRD4 inhibition blocks TGF-β-mediated cardiac fibroblast activation” (page unavailable), documents TGF-β stimulation of cultured primary adult rat ventricular fibroblasts. The cited paper therefore supports the stimulation condition, but not its application to cultured human fibroblasts. The assessment that the cultures were poor models of human cardiac fibroblast diversity is the citing authors’ own conclusion, not a finding established by this source. (LLM, conf=0.82)

  cites [40] Stratton, M. S. et al. Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation. Circ. Res. 125, 662 (2019). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [41] Bujak, M. & Frangogiannis, N. G. The role of interleukin-1 in the pathogenesis of heart disease. Arch. Immunol. Ther. Exp. (Warsz.) 57, 165 (2009). source

In the paper

“Consistent with our findings, the Srivastava laboratory has shown that Brd4 deletion in macrophages abrogates IL-1β signalling and suppresses fibroblast activation and fibrosis through a MEOX1-dependent regulatory mechanism in a pressure-overload model of HF30.”

What the sources say

• Partly supported

  In “BRD4 function in Cx3cr1+ cells during heart failure,” Brd4 deletion in Cx3cr1-positive cells reduced fibrosis after pressure overload; “BRD4 in Cx3cr1+ cells activates fibroblasts” reports reduced profibrotic fibroblast programs. The paper also links IL1B to MEOX1-dependent fibroblast activation, but “BRD4 drives proinflammatory transcription” reports decreased Il1b expression after Brd4 deletion, not that IL-1β signalling was abrogated. (LLM, conf=0.86)

  cites [30] Alexanian, M. et al. Chromatin remodelling drives immune–fibroblast crosstalk in heart failure pathogenesis. Nature https://doi.org/10.1038/s41586-024-08085-6 (2024). sourceExperimental — accuracy not yet measured

In the paper

“These findings are underscored by concurrent work establishing a role for MEOX1 in the pathogenesis of cardiac fibrosis30.”

What the sources say

• Supported

  In “IL1B drives profibrotic function via MEOX1” (page not provided), the paper reports that MEOX1 knockdown abolished the increased contractility of stimulated cardiac fibroblasts. The Conclusion (page not provided) identifies MEOX1 as a critical regulator of the stress-activated fibroblast response in heart failure, supporting the attributed role in cardiac fibrosis. (LLM, conf=0.92)

  cites [30] Alexanian, M. et al. Chromatin remodelling drives immune–fibroblast crosstalk in heart failure pathogenesis. Nature https://doi.org/10.1038/s41586-024-08085-6 (2024). source

In the paper

“We demonstrated that IL-1β was selectively expressed by CCR2+ monocytes and macrophages in the human heart, consistent with our earlier mouse studies42,43.”

What the sources say

• Partly supported

  The Results section on monocyte-derived macrophages reports higher Il1β expression in recruited CCR2+ macrophages from injured mouse hearts. It does not establish selective expression by CCR2+ monocytes and macrophages in the human heart; the paper mentions human cardiac macrophage subsets but does not report this IL-1β finding in humans. No page numbers are available in our copy. (LLM, conf=0.84)

  cites [42] Bajpai, G. et al. Tissue resident CCR2− and CCR2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ. Res. 124, 263–278 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper reports that human cardiac CCR2+ macrophages expressed more IL-1β than CCR2− macrophages (section ‘CCR2+ macrophages represent an inflammatory population’; Fig. 5a–c). It also identifies CCR2+ monocytes in the heart, but the passages do not establish that those monocytes selectively expressed IL-1β. (LLM, conf=0.87)

  cites [43] Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24, 1234–1245 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Using cross-tissue omic integration, we show that cardiac FAP+ fibroblasts display similarity to cancer-associated fibroblasts38”

What the sources say

• ?Could not verify

  The review’s ‘Expression of FAP in Tumors’ section describes FAP as a marker of cancer-associated fibroblasts. It does not address cardiac fibroblasts or compare them with cancer-associated fibroblasts; searches for cardiac FAP-positive fibroblasts and heart or myocardial fibroblasts found no passage establishing the claimed similarity. The citing sentence frames the cross-tissue comparison as the citing authors’ own finding. (LLM, conf=0.73)

  cites [38] Xin, L. et al. Fibroblast activation protein-α as a target in the bench-to-bedside diagnosis and treatment of tumors: a narrative review. Front. Oncol. 11, 3187 (2021). sourceExperimental — accuracy not yet measured

In the paper

“We used an Ang II/PE infusion model to study cardiac fibrosis which has inherent limitations3,4,7,39”

What the sources say

• Partly supported

  The passage labeled Abstract describes using AngII/PE delivered by osmotic mini-pumps to induce cardiac injury in mice and studying the resulting fibrosis. It does not identify inherent limitations of that infusion model, so it supports the model’s use but not the stated qualification. (LLM, conf=0.83)

  cites [3] Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022). sourceExperimental — accuracy not yet measured
• Partly supported

  The Fig. 3 caption (page unavailable) confirms that the paper used continuous Ang II/PE infusion in mice to induce cardiac injury and fibrosis. Neither that passage nor the searched passages on model limitations state that the infusion model has inherent limitations, so the citation supports the model identification but not the limitation claim. (LLM, conf=0.82)

  cites [4] Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (‘Cardiac fibroblasts in the scar have a unique differentiated state’; page unavailable) describes using Ang II/PE infusion and reports that it induced proliferation in fibroblasts outside the infarct scar, but not within it. This supports identification of the model and shows a context-dependent response; the paper does not state that the infusion model has inherent limitations. (LLM, conf=0.82)

  cites [7] Fu, X. et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J. Clin. Invest. 128, 2127–2143 (2018). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results (p. 3) describe a transverse aortic constriction model, while the Introduction (p. 1) identifies a limitation of earlier global Smad3-deletion studies: their lack of cell-type specificity. Searches for Ang II/PE, phenylephrine, infusion, and model limitations found no passage addressing inherent limitations of an Ang II/PE infusion model. (LLM, conf=0.77)

  cites [39] Khalil, H. et al. Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis. J. Clin. Invest. 127, 3770–3783 (2017). sourceExperimental — accuracy not yet measured

In the paper

“We then used CellOracle to build a gene regulatory network associated with HF fibroblasts, which identified enriched connectivity around RUNX1 (Extended Data Fig. 5c).”

In the paper

“Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using F9 marker genes revealed enrichment for extracellular matrix remodelling, cell–cell adhesion, protein digestion, PI3K-Akt signalling and AGE-RAGE pathways (Fig. 2f and Supplementary Table 10).”

In the paper

“AMI and chronic HF hearts contained the greatest proportion of F9 (FAP/POSTN) and F2 (myofibroblasts) fibroblasts (Fig. 2b and Extended Data Fig. 3h).”

In the paper

“Notably, the markers of F2, F4 and F9 fibroblasts increased over pseudotime in a lineage-specific manner (Extended Data Fig. 5b, bottom).”

In the paper

“We then identified genes linked to these differentially accessible peaks using paired RNA–ATAC data and found 3,167 unique linked genes (Fig. 2q and Supplementary Table 14).”

In the paper

“Projection of the velocity vector field suggested convergence toward the F2, F4 and F9 fibroblast states (Fig. 2i).”

In the paper

“We found that different fibroblast cell states were differentially enriched across myocardial regions: infarct zone (F2, F8, F9), border zone (F5, F6, F7, F10, F13) and remote zone (F11, F12) (Extended Data Fig. 4f).”

In the paper

“We found 15,373 peaks increased and 12,701 peaks reduced in HF.”

In the paper

“Intriguingly, a number of candidate GPCs composed of transcription factors were linked to dynamic regulatory elements, highlighting the potential for Multiome sequencing to identify cell type-specific gene regulatory networks.”

In the paper

“This analysis identified MEOX1 as the top transcription factor driving the F9 lineage (Fig. 2o and Supplementary Tables 12 and 13).”

In the paper

“Differential gene expression (DGE) analysis identified 11 distinct cell types (Fig. 1d and Extended Data Fig. 1b–d) with canonical gene (Fig. 1c, Extended Data Fig. 1a–c and Supplementary Table 2) and protein (Fig. 1d, Extended Data Fig. 1f and Supplementary Table 3) signatures.”

In the paper

“To assess similarity among integrated fibroblast clusters, we calculated Pearson correlation coefficients between pairwise cell states and found that most cardiac fibroblasts differed from fibroblasts found within other tissues and diseases.”

In the paper

“Next, we used Palantir to predict fibroblast differentiation endpoints, which also identified F2, F4 and F9 as terminal states with low entropy values across a range of simulation parameters (Fig. 2j and Extended Data Fig. 5a).”

In the paper

“Using cell interaction analysis and spatial transcriptomics in human heart tissue, we identified immune–fibroblast neighbourhoods within areas of fibrosis that were predicted to be driven by interleukin-1β (IL-1β) signalling from macrophages to activated fibroblasts.”

In the paper

“Donor hearts contained the greatest number of F4 (APOE/AGT) and F5 (DLK1/GPX3) fibroblasts.”

In the paper

“We merged this gene list with the pseudobulk RNA differential expression data comparing fibroblasts in donor and HF samples and found 234 overlapping genes (Fig. 2q), which included POSTN, MEOX1 and RUNX1 (Supplementary Table 15).”

In the paper

“Pseudobulk DGE analysis at the patient level showed strong differences between healthy donor and heart failure (HF) (AMI, ICM, NICM) conditions within fibroblasts, endothelial cells, smooth muscle cells (SMCs) and pericytes, and myeloid cells (Fig. 1f and Supplementary Table 4).”

In the paper

“Consistent with this finding, RUNX1 was co-expressed with POSTN at the single-cell and patient levels (Extended Data Figs. 4b and 5d) and we previously showed expansion of RUNX1-expressing cells in human HF29.”

In the paper

“Intriguingly, we observed that JQ1 treatment, which resulted in improved left ventricle systolic function and abrogation of fibrosis, was associated with the loss of F9 fibroblasts.”

In the paper

“Mapping scores were strong across most cell states except for F5, F6 and F7 fibroblasts, which were poorly represented in the mouse data (Fig. 3a and Extended Data Fig. 6a).”

In the paper

“Unbiased clustering of our CITE-seq data identified 13 distinct fibroblast cell states (Fig. 2a), marked by Pl16/CCDC80/FBLN1 (F1, ground state), ACTA2/TAGLN (F2, myofibroblasts), CCL2/THBS1 (F3), APOE/AGT (F4), DLK1/GPX3 (F5), PTGDS/GPC3 (F6), APOD/IGFBP5 (F7), GDF15/ATF5 (F8), FAP/POSTN (F9), ISG15/MX1 (F10), PLA2G2A (F11), PCOLCE2/MFAP5 (F12) and PRG4/CXCL14 (F13) (Fig. 2b).”

In the paper

“Genes differentially expressed in the more abundant cell types (cardiomyocytes, myeloid, fibroblasts, endothelium, pericytes, T and natural killer cells, and endocardium) mapped to unique ATAC clusters (Extended Data Fig. 2d–f).”

In the paper

“FAP expression progressively increases along the F9 lineage.”

In the paper

“Moreover, MEOX1 was co-expressed with RUNX1 and POSTN along the F9 lineage.”

In the paper

“Ang II/PE infusion resulted in diminished interstitial fibrosis in IL-1βflox/flox CCR2creERT2 mice compared with IL-1βflox/flox mice (Fig. 5e).”

In the paper

“We found strong correlation between macrophage IL-1β and fibroblast POSTN expression in individual cardiac tissue specimens and detected enriched NF-kB pathway signalling in corresponding regions (Extended Data Fig. 9h).”

In the paper

“SMCs, pericytes and endothelial cells co-localized in a distinct perivascular niche (Fig. 4e, Extended Data Fig. 9a–g and Supplementary Tables 21 and 22).”

In the paper

“Quantification of flow cytometry data revealed an increase in the proportion of FAP+ fibroblasts in Ang II/PE-treated animals that received isotype antibodies compared with corresponding controls.”

In the paper

“Ang II/PE-treated mice had greater fibroblast activator protein inhibitor (FAPi) signal compared with sham.”

In the paper

“Using spatial transcriptomic data from human hearts, we showed that CCR2+ monocytes and macrophages co-localize with FAP/POSTN fibroblasts, forming an immune–fibroblast niche.”

In the paper

“Anti-IL-1β mAb treatment also reduced the expression of the myofibroblast marker, Acta2.”

In the paper

“Ang II/PE infusion resulted in increased interstitial fibrosis in control mice compared with shams.”

In the paper

“Importantly, there were fewer FAP+ fibroblasts in IL-1Rflox/flox Dermo1Cre mice compared with control mice (Fig. 4k and Supplementary Fig. 6).”

In the paper

“After deconvolution, we calculated cell–cell correlations and found fibroblasts most strongly co-localize with myeloid cells and T cells, forming an immune–fibroblast niche.”

In the paper

“Notably, the anti-IL-1β mAb group had fewer Postn+ cells (Fib 1; Extended Data Fig. 10e, bottom panel) and decreased expression of key pro-fibrotic genes such as Aebp1, Fap, Postn, Thbs1, Meox1, Runx1, Clip2, Comp, Col1a1, Thy1 and Cthrc1 compared with isotype-treated mice.”

In the paper

“each of which co-localized in the infarct region using spatial transcriptomics data (Fig. 4c and Extended Data Fig. 8g,h).”

In the paper

“POSTN immunostaining and quantitative PCR from left-ventricle tissue showed decreased POSTN expression at the protein and RNA levels, corroborating our scRNA-seq (Extended Data Fig. 10k,l).”

In the paper

“Mice treated with anti-IL-1β mAb demonstrated less 68Ga-FAPi-46 uptake compared with mice treated with isotype control (Fig. 5h).”

In the paper

“We found increased cardiomyocyte cross-sectional area in Ang II/PE-treated controls compared with shams.”

In the paper

“We used immunofluorescence for CCR2/FAP/CD68 in human left-ventricle sections to show co-localization of FAP+ fibroblasts with CCR2+ macrophages in the failing left ventricle (Fig. 4g).”

In the paper

“Notably, with Ang II/PE infusion, there were fewer FAP+ fibroblasts in IL-1βflox/flox CCR2creERT2 mice compared with IL-1βflox/flox mice at day 7 (Fig. 5b).”

In the paper

“decreased expression of key pro-fibrotic genes such as Aebp1, Fap, Postn, Thbs1, Meox1, Runx1, Clip2, Comp, Col1a1, Thy1 and Cthrc1 compared with isotype-treated mice.”

In the paper

“we observed reduced trichrome staining in Ang II/PE-treated IL-1Rflox/floxDermo1Cre mice compared with Ang II/PE-treated controls (Fig. 4l).”

In the paper

“IL-1R was expressed within cardiac fibroblasts including F9 fibroblasts as well as the endocardium and a subset of endothelial cells (Extended Data Fig. 9i).”

In the paper

“Cells were clustered into ten transcriptionally distinct fibroblast cell states (Extended Data Fig. 10f–h and Supplementary Table 26).”

In the paper

“We found seven transcriptionally distinct fibroblast cell states (Fig. 5i, Extended Data Fig. 10a–c and Supplementary Table 24) and expansion of Postn+ fibroblasts in Ang II/PE relative to sham (Extended Data Fig. 10d,e).”

In the paper

“PHCFs and PHDFs recovered a broader diversity of cell states compared with iHCFs.”

In the paper

“Quantification showed more CCR2+ cells in areas with high numbers of POSTN+ cells compared with areas with fewer POSTN+ cells (Fig. 4i).”

In the paper

“Both mouse models displayed reduced FAP+ fibroblasts, diminished fibrosis and improved cardiac function.”

In the paper

“We detected differences in gene expression in both the FAP+ and FAP− fibroblasts following anti-IL-1β mAb treatment (Extended Data Fig. 10j).”

In the paper

“We observed a significant decrease in E/e′ and end systolic volume with a significant improvement in fractional shortening and ejection fraction in IL-1βflox/flox CCR2creERT2 mice compared with IL-1βflox/flox mice (Fig. 5c,d).”

In the paper

“Linear regression analysis showed a strong correlation between pseudobulk macrophage IL-1β expression with fibroblast POSTN expression (Fig. 4h).”

In the paper

“Collectively, mouse fibroblasts present across cardiac injury models showed substantially greater transcriptional similarity to human cardiac fibroblasts relative to human cell culture preparations (Fig. 3h and Extended Data Fig. 7d,e).”

In the paper

“and recapitulated expansion of Fap- and Postn-expressing fibroblasts following injury.”

In the paper

“All cultured cell lines displayed a limited ability to recapitulate human cardiac fibroblast states.”

In the paper

“FAP− fibroblasts showed reduced expression of ApoE, Gdf15, Ptgds, Ccl2 and Prg4 following anti-IL-1β mAb treatment (Extended Data Fig. 10j).”

In the paper

“Importantly, we observed a reduction in FAP+ fibroblasts in Ang II/PE-treated mice that received anti-IL-1β mAb compared with Ang II/PE-treated mice that received isotype antibody (Fig. 5g).”

In the paper

“Both mouse models displayed reduced FAP+ fibroblasts, diminished fibrosis and improved cardiac function.”

In the paper

“This gene set was expressed predominately in Postn+ fibroblasts (Fig. 5i).”

In the paper

“However, Tagln and Sparc were not significantly impacted (Fig. 5j).”

In the paper

“We further characterized putative epigenetic regulators of FAP/POSTN fibroblasts and found MEOX1 to be the most enriched transcription factor.”

In the paper

“Anti-IL-1β mAb treatment increased the expression of myofibroblast markers (including Tagln, Acta2 and Svep1) in FAP+ fibroblasts (Extended Data Fig. 10j)”

In the paper

“Pathway analysis suggested reductions in TGFβ regulation of extracellular matrix in the anti-IL-1β mAb group relative to isotype controls (Fig. 5k and Supplementary Table 25).”

In the paper

“We found that mouse models contained many of the fibroblast populations found in the human heart”

In the paper

“In vivo, IL-1β expression was conserved in mouse CCR2+ monocytes and macrophages in the Ang II/PE infusion model (Fig. 4d).”

In the paper

“and detected enriched NF-kB pathway signalling in corresponding regions (Extended Data Fig. 9h).”

In the paper

“Using cell–cell interaction analysis, we identified enrichment of IL-1β and TGFβ signalling in fibroblasts in HF.”

In the paper

“Within the FAP+ population, isotype-treated animals displayed increased expression of Fap, Thbs4, Isg15, Col1a1 and Cola3.”

In the paper

“Quantification of flow cytometry data revealed an increase in the proportion of FAP+ fibroblasts in Ang II/PE-treated animals compared with sham surgeries.”

In the paper

“and expansion of Postn+ fibroblasts in Ang II/PE relative to sham (Extended Data Fig. 10d,e).”

In the paper

“after 28 d of Ang II/PE infusion via osmotic minipumps, anti-IL-1β mAb treatment decreased cardiac fibrosis (Fig. 5l and Extended Data Fig. 10m).”

In the paper

“We focused on signals received by fibroblasts from any cell type and identified TGFβ and IL-1β as the strongest predicted signals (Fig. 4a).”

In the paper

“However, there was a significant decrease in cardiomyocyte size in Ang II/PE-treated IL-1Rflox/floxDermo1Cre mice compared with Ang II/PE-treated controls (Fig. 4m).”

In the paper

“Blocking IL-1β signalling does not fully ameliorate cardiac fibrosis”

In the paper

“Collectively, these findings predict that FAP/POSTN (F9) fibroblasts are regulated by RUNX1 and MEOX1.”

In the paper

“These data suggest that FAP/POSTN (F9) fibroblasts were distinct from myofibroblasts (F2) and other predicted terminal fibroblast cell states.”

In the paper

“Fibroblast cell state clustering was validated by gene set and surface protein signatures (Extended Data Fig. 3a–e and Supplementary Tables 8 and 9).”

In the paper

“Finally, we demonstrated that IL-1β signalling from C-C chemokine receptor type 2 (CCR2) macrophages to fibroblasts is causally linked to cardiac fibrosis in vivo.”

In the paper

“We then validated that F2 and F9 fibroblast populations are distinct cell types using RNAscope and immunofluorescence for POSTN and ACTA2, respectively, in the human infarct tissue (Fig. 2k).”

In the paper

“These findings implicate F9 fibroblasts as a potential pathogenic cell state.”

In the paper

“and contributes to cardiac fibrosis.”

In the paper

“Although we chose to include patients of diverse ethnicities, sexes and ages in the generation of the human dataset, we did not have adequate an sample size available to independently assess the effects of these variables.”

In the paper

“highlighting a selective role of IL-1β signalling in the FAP/POSTN fibroblast lineage.”

In the paper

“governed by inflammatory cytokines derived from monocytes and derived macrophages”

In the paper

“Collectively, these findings implicate CCR2+ monocytes and macrophages as key regulators of fibrosis in HF”

In the paper

“We used CITE-seq, Multiome and spatial transcriptomics to dissect fibroblast cell states that emerge following AMI and in chronic HF and identified a fibroblast trajectory marked by FAP and POSTN expression that is independent of myofibroblasts”

In the paper

“and used a tamoxifen dosing strategy to specifically target blood monocytes and monocyte-derived macrophages34,35.”

What the sources say

• ?Not checked — no full text of the sourcecites [34] Kadyrov, F. F. et al. Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury. Preprint at bioRxiv https://doi.org/10.1101/2022.08.04.502542 (2023). source
• ?Not checked — no full text of the sourcecites [35] Koenig, A. L. et al. Genetic mapping of monocyte fate decisions following myocardial infarction. Preprint at bioRxiv https://doi.org/10.1101/2023.12.24.573263 (2023). source

In the paper

“and highlight the potential for targeting inflammatory mediators including IL-1β.”

In the paper

“Quantitative PCR verified decreased IL-1R expression in fibroblasts but not macrophages (Extended Data Fig. 9j).”

In the paper

“These data indicate that mouse cardiac injury models are a reasonable experimental model to explore mechanisms involved in FAP/POSTN (F9) fibroblast emergence and cardiac fibrosis.”

In the paper

“Collectively, our findings highlight a promising role for immunomodulators in targeting cardiac fibrosis.”

In the paper

“We demonstrated that IL-1β produced by CCR2+ monocytes and macrophages regulates FAP/POSTN fibroblast specification by directly signalling to cardiac fibroblasts.”

In the paper

“suggesting there may be more factors that contribute to cardiac fibrosis.”