Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context

Setten, Elisa; Castagna, Alessandra; Nava-Sedeño, Josué Manik; Weber, Jonathan; Carriero, Roberta; Reppas, Andreas I.; Volk, Valery; Schmitz, Jessica; Gwinner, Wilfried; Hatzikirou, Haralampos; Feuerhake, Friedrich; Locati, Massimo

doi:10.1038/s41467-022-34241-5

Cited by 15 publications

(16 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Macrophage polarization accompanies the progressively changing tissue microenvironment and macrophages modulate fibroblast activation and ECM-producing myofibroblast trans-differentiation through soluble factors or direct cell-cell interaction [1][2][3][4]. The outcome of fibrosis is directly dependent on tissue macrophage heterogeneity as different macrophage subpopulations can have contrasting modulatory effects on fibrogenesis [5].…”

Section: Introductionmentioning

confidence: 99%

Systems Level Identification of a Matrisome-Associated Macrophage Polarization State in Multi-Organ Fibrosis

Huang

Mishra

Park

et al. 2022

Preprint

View full text Add to dashboard Cite

Tissue fibrosis affects multiple organs and involves a master-regulatory role of macrophages which respond to an initial inflammatory insult common in all forms of fibrosis. The recently unraveled multiorgan heterogeneity of macrophages in healthy and fibrotic human disease suggest that tissue resident macrophages, expressing osteopontin (SPP1), associate with lung and liver fibrosis. However, the conservation of this SPP1+ macrophage population across different tissues, and its specificity to fibrotic diseases with different etiologies remain unclear. Integrating 13 single cell RNA-sequencing datasets to profile 225,985 tissue macrophages from healthy and fibrotic heart, lung, liver, kidney, skin and endometrium, we extended the association of SPP1+ macrophages with fibrosis to all these tissues. We also identified a subpopulation expressing matrisome-associated genes (e.g., matrix metalloproteinases and their tissue inhibitors), functionally enriched for ECM remodeling and cell metabolism, representative of a matrisome-associated macrophage (MAM) polarization state within SPP1+ macrophages. Importantly, the MAM polarization state follows a differentiation trajectory from SPP1+ macrophages, which was conserved across all fibrotic tissues and driven by NFATC1 and HIVEP3 regulons. Unlike SPP1+ macrophages, the MAM polarization state shows a positive association with ageing in mice and humans, and across multiple tissues during homeostasis. These results suggest an advanced, agedependent polarization state of SPP1+ macrophages in fibrotic tissues as a result of prolonged inflammatory cues within each tissue microenvironment.

show abstract

Section: Introductionmentioning

confidence: 99%

Systems Level Identification of a Matrisome-Associated Macrophage Polarization State in Multi-Organ Fibrosis

Huang

Mishra

Park

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The finding of cold fibrosis after acute MI raises the question of which other pathologies might show hot fibrosis. Recent histological analysis of human transplanted kidneys indicated hot and cold fibrosis states that are spatially-dependent (Setten et al, 2022). The same study extended the mathematical model (Adler et al, 2020) to include the effects of local hypoxia and inflammation status on the cell circuit.…”

Section: Discussionmentioning

confidence: 99%

Circuit to target approach defines an autocrine myofibroblast loop that drives cardiac fibrosis

Miyara

Adler

Bassat

et al. 2023

Preprint

View full text Add to dashboard Cite

Fibrosis is a broad pathology of excessive scarring with substantial medical implications. The fibrotic scar is produced by myofibroblasts that interact with macrophages. Fibrosis is a complex process involving thousands of factors, therefore, to better understand fibrosis and develop new therapeutic approaches, it is necessary to simplify and clarify the underlying concepts. Recently, we described a mathematical model for a macrophage-myofibroblast cell circuit, predicting two types of fibrosis - hot fibrosis with abundant macrophages and myofibroblasts, and cold fibrosis dominated by myofibroblasts alone. To test these concepts and intervention strategies in a medically relevant system, we use a widely studied in-vivo injury model for fibrosis, myocardial infarction (MI). We show that cold fibrosis is the final outcome of MI in both mice and pigs and demonstrate that fibrosis can shift toward healing in regenerative settings. MI begind with an increase of myofibroblasts and macrophages, followed by macrophage decline leading to persistent cold fibrosis (only myofibroblasts). During this process, fibroblasts, unlike macrophages, acquire distinct fate changes. Using mathematical modeling we predict that targeting of the autocrine signal for myofibroblast division could block cold fibrosis. We identify TIMP1 as an autocrine cardiac myofibroblast growth factor in-vitro. Treatment of adult mice after MI with anti-TIMP1 antibodies reduces fibrosis in-vivo. This study shows the utility of the concepts of hot and cold fibrosis and the feasibility of our circuit-to-target approach to reduce fibrosis after acute cardiac injury by inhibiting the myofibroblast autocrine loop.

show abstract

“…Macrophages and fibroblasts have important interactions in tissues [39][40][41] , and age has been shown to negatively affect fibroblast phenotype and function 42,43 . We explored age-related changes in cell interactions in the renal capsule, focusing on TLF + macrophages, fibroblasts and CD8 T cells, as those populations showed most changes in cell counts in the aged renal capsule.…”

Section: Discussionmentioning

confidence: 99%

The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging

Korin,

Avraham,

Moncada

et al. 2023

Preprint

View full text Add to dashboard Cite

The kidney is a complex organ that governs many physiological parameters. It is roughly divided into three parts, the renal pelvis, medulla, and cortex. Covering the cortex is the renal capsule, a serosal tissue that provides protection and forms a barrier for the kidney. Serosal tissues of many organs have been recently shown to play a vital role in homeostasis and disease. Analyses of the cells that reside in these tissues have identified distinct cell types with unique phenotypes. Surprisingly, despite the importance of serosal tissues, little is known about cells of the renal capsule. Here, we characterized this niche and found that it is mainly comprised of fibroblasts and macrophages, but also includes many other diverse cell types. Characterizing renal capsule-associated macrophages, we found that they consist of a distinct subset (i.e., TLF+ macrophages) that is nearly absent in the kidney parenchyma. Injury, disease, and other changes within the kidney, affected the cell composition and phenotype of the renal capsule, indicating its dynamic and vibrant response to changes within the organ parenchyma. Lastly, we studied age-related changes in the renal capsule and found that aging affected the cell composition and pro-inflammatory phenotype of macrophages, increased CD8 T cells and other lymphocyte counts, and promoted a senescence-associated phenotype in fibroblasts. Taken together, our data illustrate the complexity and heterogeneity of the renal capsule and its underlying changes during aging and disease, improving our understanding of the kidney serosa that may be valuable for novel renal therapies.

show abstract

Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context

Cited by 15 publications

References 47 publications

Systems Level Identification of a Matrisome-Associated Macrophage Polarization State in Multi-Organ Fibrosis

Systems Level Identification of a Matrisome-Associated Macrophage Polarization State in Multi-Organ Fibrosis

Circuit to target approach defines an autocrine myofibroblast loop that drives cardiac fibrosis

The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging

Contact Info

Product

Resources

About