Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy

• DOI: 10.1172/jci181630
• Publication Date: 2025-01-01T19:00:42Z
• Authors: Bryan Z. Wang; Margaretha A.J. M...; 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. Cunn...; Gavin Y. Oudit; Barry M. Fine; Christine E. Seidman; Jonathan G. Seidman; Gordana Vunjak-No...
• Keywords: Dilated Cardiomyopathy; Cardiac Fibrosis; BAG3; Myocardial fibrosis

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