Cardiac fibroblast sub-types in vitro reflect pathological cardiac remodeling in vivo
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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.
|Tidsskrift||Matrix Biology Plus|
|Status||Udgivet - 2022|
KMH has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 795390. KJW is supported by The Novo Nordisk Foundation Center for Stem Cell Biology [NNF17CC0027852] and the Independent Research Fund Denmark [0135-00243B]. The work was also supported by Independent Research Fund Denmark (DFF-0199-00001B) to AL.
The authors acknowledge support from the Gill Cardiovascular Biorepository at the University of Kentucky and from the patients, organ donors, and families that donated samples. Funding: NIH TR033173, HL133359, HL146676 (KSC), AHA TP135689 (KSC), and Penny Warren Award for Clinical and Translational Research.
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kate Herum reports financial support was provided by Marie Sklodowska-Curie grant (AU Horizon 2020). Kyoung Jae Won reports financial support was provided by Novo Nordisk Foundation. Alicia Lundby reports financial support was provided by Independent Research Fund Denmark. Kenneth S. Campbell reports was provided by National Institutes of Health. Kyoung Jae Won reports financial support was provided by Independent Research Fund Denmark.
© 2022 The Authors