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 (), thymocyte differentiation antigen 1 (THY-1), and endothelin receptor A () predicted to be driven by a gene regulatory network. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different 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 transcription factor perturbation and 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.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9900986 | PMC |
http://dx.doi.org/10.21203/rs.3.rs-2402606/v1 | DOI Listing |
J Anim Physiol Anim Nutr (Berl)
December 2024
Department of Poultry Production, Faculty of Agriculture, Assiut University, Assiut, Egypt.
Lepidium meyenii (Maca) is a plant that has nutritional benefits and increases the effectiveness of male reproduction. In this study, oxidative stress-exposed New Zealand rabbits were used to assess the ameliorative effects of daily Maca ingestion on testicular and epididymal tissues as well as the quality of fresh and frozen/thawed sperm. Twenty-four 40-week-old, healthy New Zealand white male rabbits were divided into four groups.
View Article and Find Full Text PDFCurr Stem Cell Res Ther
December 2024
National Institute for Drug Clinical Trial, Beijing Tongren Hospital, Capital Medical University, No.1 Dongjiaominxiang Road, Beijing, 100730, China.
Background: Idiopathic Nephrotic Syndrome (INS) is a common kidney disease in children, and the main clinical manifestations are hypoproteinaemia, proteinuria, hyperlipidaemia, and oedema. Mesenchymal Stem Cells (MSCs) are involved in tissue repair, protection against fibrosis, and immune modulation but have rarely been studied in INS.
Objective: This study aimed to explore the therapeutic potential of stem cells derived from human exfoliated deciduous teeth (SHEDs) in INS using an adriamycin-induced nephropathy (AN) rat model.
Br J Pharmacol
December 2024
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Background And Purpose: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiovascular benefits in diabetic patients, but the underlying mechanisms remain incompletely understood. Semaglutide, a novel long-acting GLP-1RA, has shown a reduced risk of cardiovascular events. Based on these results, we investigated the therapeutic potential of semaglutide in diabetic cardiomyopathy and sought to elucidate the underlying mechanisms.
View Article and Find Full Text PDFCell Mol Gastroenterol Hepatol
December 2024
Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Broad Institute, Cambridge, MA. Electronic address:
Background And Aims: Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms.
Methods: ACLF was triggered by a single alcohol binge (5g/Kg) in a bile duct ligation (BDL) liver fibrosis murine model.
Toxicol Appl Pharmacol
December 2024
College of Medicine, Graduate School, Kyung Hee University, 02447, Republic of Korea; Division of Cardiology, Department of Internal Medicine, Kyung-Hee University Hospital, Kyung Hee University, 02447, Republic of Korea. Electronic address:
In the current study, we dosed Didecyldimethylammonium chloride (DDAC) in mice by pharyngeal aspiration for 28 days or 90 days (weekly) and tried to elucidate the relationship between lamellar body formation and the lesions. When exposed for 28 days (0, 5, 10, 50, and 100 μg/head), all the mice in the 50 and 100 μg/head groups died since Day 2 after the third dosing (Day 16 after the first dosing). Edema, necrosis of bronchiolar and alveolar epithelium, and fibrinous exudate were observed in the lungs of all the dead mice, and chronic inflammatory lesions were observed in the lung tissues of alive mice.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!