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Updated: Sep 7, 2025
Fabrication of 3D Cardiac Microtissue Arrays using Human iPSC-Derived Cardiomyocytes, Cardiac Fibroblasts, and Endothelial Cells
Published on: March 14, 2021
Cardiac fibroblast sub-types in vitro reflect pathological cardiac remodeling in vivo
Kate Møller Herum1, Guangzheng Weng1, Konstantin Kahnert2
1Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark.
Insights
This study identifies a 12-gene signature for heart failure (HF) that reflects fibroblast activation. These findings reveal shared characteristics of cardiac fibroblast activation across human disease, animal models, and cell cultures.
Area of Science:
- Cardiovascular Biology
- Fibrosis Research
- Cellular and Molecular Medicine
Background:
- Fibrosis is a hallmark of many heart diseases, but the diversity of activated fibroblast subtypes and their in vitro modeling remains unclear.
- Understanding fibroblast heterogeneity is crucial for developing targeted therapies for fibrotic heart conditions.
Purpose of the Study:
- To identify specific gene expression profiles of activated cardiac fibroblasts in heart failure (HF) patients.
- To investigate the extent to which in vitro models recapitulate fibroblast activation seen in human HF and animal models.
Main Methods:
- Analysis of 82 fibrosis-related genes in 65 HF patients and healthy controls.
- Single-cell transcriptomic analysis of in vitro activated mouse cardiac fibroblasts.
- Utilized time trajectory analysis and population markers for clustering disease stages in a murine myocardial infarct model.
Main Results:
- A 12-gene panel effectively distinguished HF patients from controls, outperforming hydroxyproline content measurement.
- Identified distinct fibroblast subpopulations in vitro, including a precursor population developing into extracellular matrix-producing cells.
- The 12-gene HF profile closely matched the in vitro fibroblast subset with high extracellular matrix production, and markers clustered disease stages in a murine model.
Conclusions:
- Major features of cardiac fibroblast activation are conserved across human heart failure, murine disease models, and primary murine cardiac fibroblast cultures.
- The identified 12-gene signature provides a potential biomarker for HF and insights into fibroblast heterogeneity.
- In vitro models can effectively recapitulate key aspects of cardiac fibroblast activation relevant to heart disease.
Abstract:
Many heart diseases are associated with fibrosis, but it is unclear whether different types of heart disease correlate with different subtypes of activated fibroblasts and to which extent such diversity is modeled during in vitro activation of primary cardiac fibroblasts. Analyzing the expression of 82 fibrosis related genes in 65 heart failure (HF) patients, we identified a panel of 12 genes clearly distinguishing HF patients better from healthy controls than measurement of the collagen-related hydroxyproline content. A subcluster enriched in ischemic HF was recognized, but not for diabetes, high BMI, or gender. Single-cell transcriptomic analysis of in vitro activated mouse cardiac fibroblasts distinguished 6 subpopulations, including a contractile Acta2high precursor population, which was predicted by time trajectory analysis to develop into Acta2low subpopulations with high production of extracellular matrix molecules. The 12 gene profile identified in HF patients showed highest similarity to the fibroblast subset with the strongest expression of extracellular matrix molecules. Population markers identified were furthermore able to clearly cluster different disease stages in a murine model for myocardial infarct. These data suggest that major features of cardiac fibroblast activation in heart failure patients, in murine heart disease models, and in cell culture of primary murine cardiac fibroblast are shared.
