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Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy
Bryan Z. Wang, … , Jonathan G. Seidman, Gordana Vunjak-Novakovic
Bryan Z. Wang, … , Jonathan G. Seidman, Gordana Vunjak-Novakovic
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(1):e181630. https://doi.org/10.1172/JCI181630.
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Research Article Cardiology

Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy

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Abstract

Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function of BAG3 in other cardiac cell types is understudied. In this study, we used an isogenic pair of BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate the role of BAG3 in hiPSC-derived cardiac fibroblasts (CFs). Analysis of cell type–specific conditional knockout engineered heart tissues revealed an essential contribution of CF BAG3 to contractility and cardiac fibrosis, recapitulating the phenotype of DCM. In BAG3–/– CFs, we observed an increased sensitivity to TGF-β signaling and activation of a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, we showed that loss of BAG3 increased transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 and mediating its ubiquitination and proteasomal degradation. To further validate these results, we performed single-nucleus RNA sequencing of cardiac tissue from DCM patients carrying pathogenic BAG3 variants. BAG3 pathogenic variants increased fibrotic gene expression in CFs. Together, these results extend our understanding of the roles of BAG3 in heart disease beyond the cardiomyocyte-centric view and highlight the ability of tissue-engineered hiPSC models to elucidate cell type–specific aspects of cardiac disease.

Authors

Bryan Z. Wang, Margaretha A.J. Morsink, Seong Won Kim, Lori J. Luo, Xiaokan Zhang, Rajesh Kumar Soni, Roberta I. Lock, Jenny Rao, Youngbin Kim, Anran Zhang, Meraj Neyazi, Joshua M. Gorham, Yuri Kim, Kemar Brown, Daniel M. DeLaughter, Qi Zhang, Barbara McDonough, Josephine M. Watkins, Katherine M. Cunningham, Gavin Y. Oudit, Barry M. Fine, Christine E. Seidman, Jonathan G. Seidman, Gordana Vunjak-Novakovic

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Figure 5

Gene expression changes in BAG3 fibroblasts indicate increased TGF-β signaling.

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Gene expression changes in BAG3 fibroblasts indicate increased TGF-β sig...
(A) Uniform manifold approximation and projection (UMAP) visualization of multiplexed snRNA-Seq data of cultured CFs, color-coded based on their respective genotypes. (B) Averaged and normalized expression of fibrosis- and TGF-β–related genes. Median values are denoted by black horizontal bars. The interquartile range is illustrated by the upper and lower boundaries of the box. The highest and lowest values are indicated by the top and bottom ends of the vertical lines. Adjusted P values from edgeR analysis are provided at the top. (C) UMAP of non-failing control and DCM-affected left ventricles, distinguished by their assigned cell types. (D) UMAP of fibroblasts, with color indicating their respective cell states. (E and F) Dot plot illustrating the differentially expressed genes in BAG3+/+, BAG3+/–, and BAG3–/– hiPSC-CFs (E) and human tissue fibroblasts (F). Genes highlighted in red indicate significantly differential expression in the proteomics of BAG3–/– hiPSC-CFs. The size of each dot represents the fraction of nuclei expressing each gene, and colors indicate log2 fold change. Adjusted P values from edgeR analysis are displayed on top of each dot. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (G) Representative images from staining of explanted BAG3 DCM (n = 4) hearts and non-failing control (NFC) hearts (n = 4) with Masson’s trichrome and Picrosirius red (PSR) staining. Scale bars: 50 μm. (H) Quantification of fibrosis in trichrome images. Each dot represents the average fibrosis present in patient samples from several histological slices. n = 4 for both NFC and BAG3-mutant DCM patients. (I) Quantification of fibrosis in PSR images. n = 4 for both NFC and BAG3-mutant DCM patients. **P < 0.01 by 2-tailed Student’s t test (H and I).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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