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3D Biomechanics and Epigenomics Reveal Atypical Fibroblast Responses in Cardiometabolic Disease

ABSTRACT: Cell behavior is influenced by substrate stiffness and cell-cell and cell-environment interactions. The limitations of two-dimensional (2D) culture, such as its inability to fully capture the complexity of cell interactions and tissue structure, highlights the necessity of three-dimensional (3D) cell culture. This explicitly applies to ‘disease modeling in a dish’ platforms for translational studies. 3D bioprinting demonstrates significant potential in recapitulating the intricate physiological environments of human tissues in both healthy and pathological states. With the alarming rise in obesity, addressing systemic pathophysiological dysfunction beyond adipose tissue itself, such as the heart, is inevitable. To capture cellular and tissue-level responses to overnutrition, we employed state-of-the-art 3D bioprinting technology to understand the acute response of 3D matrix-embedded human cardiac fibroblasts (HCFs) to a ‘high-fat diet’ mimic. Chromatin accessibility profiling revealed that excess fatty acid (FA) exposure in 2D induces a non-canonical extracellular matrix (ECM) gene program that is minimally expressed in healthy adult myocardium. In contrast, 3D cultures exhibited reduced fibroblast proliferation and blunted transcriptional responses to the impact of biomechanical cues under metabolic stress, reflecting a more quiescent and physiologically relevant phenotype. Furthermore, we incorporated human induced pluripotent stem cell-derived cardiac fibroblasts (iPSC-CFs), which mirrored key transcriptional changes, including sex-dependent gene regulation. Notably, male iPSC-CFs showed stronger fibrotic gene induction than females, reinforcing the need to account for biological sex in disease modeling. Together, our results highlight the limitations of 2D systems and demonstrate that 3D-bioprinted platforms provide a scalable, physiologically relevant tool for investigating cardiometabolic diseases and therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304619 | GEO | 2025/10/10

REPOSITORIES: GEO

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Project description:The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional (2D) monolayers on plastic. However, many cellular features are impaired in these unnatural conditions and big alterations in gene expression in comparison to tumors have been reported. Three-dimensional (3D) cell culture models have become increasingly popular and are suggested to be better models than 2D monolayers due to improved cell-to-cell contacts and structures that resemble in vivo architecture. The aim of this study was to develop a simple high-throughput 3D drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in 2D, in polyHEMA coated anchorage independent 3D models and in Matrigel on-top 3D cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating or they were allowed to grow in 3D for four days prior to the drug treatment. Big variations in drug responses were observed between the models indicating that comparisons of culture model influenced drug sensitivities cannot be made based on effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in 2D cultures, while responses of cells grown in polyHEMA resembled those of 2D. Furthermore, comparison of gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study we also suggest that 3D cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives for traditional 2D screens towards better comparability to in vivo state. Gene expression analysis of JIMT1 breast cancer cells cultured as xenografts for 43 days, in two dimensional cultures for seven days (2D7d), in polyHEMA three dimensional cell culture models for four and seven days (PH7d and PH7d), and in Matrigel three dimensional cultures for four and seven days (MG4d and MG7d). Two biological replicates was included for each sample.

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3D Biomechanics and Epigenomics Reveal Atypical Fibroblast Responses in Cardiometabolic Disease

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