C-C chemokine receptor type 2 (CCR2-) cardiac-resident macrophages (CCR2- cRMs) are known to promote cardiac repair after myocardial infarction (MI). However, the substantial depletion and slow recovery of CCR2- cRMs pose significant barriers in cardiac recovery. Here, we construct a functional conductive cardiac patch (CCP) that can provide exogenously elastic conductive microenvironment and induce endogenously reparative microenvironment mediated by CCR2- cRMs for MI repair. This CCP exhibits suitable mechanical properties, conductivity, and high water retention, reminiscent of natural myocardium, which can actively engage in modulating CCR2- cRM renewal and their cell crosstalk. The functional CCP can promote the expression of Connexin43 between CCR2- cRMs and cardiomyocytes (CMs) and regulate paracrine signaling to activate epicardial cell epithelial-to-mesenchymal transition (EMT) toward endothelial cells using rat and Wt1CreERT2 transgenic lineage tracing mice. Overall, this study provides a promising strategy to construct a synergistic reparative microenvironment for MI repair.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

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.

Untethered electrical stimulation or pacing of the heart is of critical importance in addressing the pressing needs of cardiovascular diseases in both clinical therapies and fundamental studies. Among various stimulation methods, light illumination-induced electrical stimulation via photoelectric effect without any genetic modifications to beating cells/tissues or whole heart has profound benefits. However, a critical bottleneck lies in the lack of a suitable material with tissue-like mechanical softness and deformability and sufficient optoelectronic performances toward effective stimulation. Here, we introduce an ultrathin (<500 nm), stretchy, and self-adhesive rubbery bio-optoelectronic stimulator (RBOES) in a bilayer construct of a rubbery semiconducting nanofilm and a transparent, stretchable gold nanomesh conductor. The RBOES could maintain its optoelectronic performance when it was stretched by 20%. The RBOES was validated to effectively accelerate the beating of the human induced pluripotent stem cell-derived cardiomyocytes. Furthermore, acceleration of ex vivo perfused rat hearts by optoelectronic stimulation with the self-adhered RBOES was achieved with repetitive pulsed light illumination.

Cardiac endothelial cells are essential for heart development, and disruption of this process can lead to congenital heart disease (CHD). However, how microRNAs influence cardiac endothelial cells in CHD remains unclear. This study identified elevated microRNA-187 (miR-187) expression in embryonic heart endothelial cells from CHD fetuses. Using a conditional knockin model, we showed that increased miR-187 levels in embryonic endothelial cells induce CHD in homozygous fetal mice, closely mirroring human CHD. Mechanistically, miR-187 targets NIPBL, which is responsible for recruiting the cohesin complex and facilitating chromatin accessibility. Consequently, the endothelial cell-specific upregulation of miR-187 inhibited NIPBL, leading to reduced chromatin accessibility and impaired gene expression, which hindered endothelial cell development and ultimately caused heart septal defects and reduced heart size both in vitro and in vivo. Importantly, exogenous miR-187 expression in human cardiac organoids mimicked developmental defects in the cardiac endothelial cells, and this was reversible by NIPBL replenishment. Our findings establish the miR-187/NIPBL axis as a potent regulator that inhibits cardiac endothelial cell development by attenuating the transcription of numerous endothelial genes, with our mouse and human cardiac organoid models effectively replicating severe defects from minor perturbations. This discovery suggests that targeting the miR-187/NIPBL pathway could offer a promising therapeutic approach for CHD.

Illuminating the precise stepwise genetic programs directing cardiac development provides insights into the mechanisms of congenital heart disease and strategies for cardiac regenerative therapies. Here, we integrate in vitro and in vivo human single-cell multi-omic studies with high-throughput functional genomic screening to reveal dynamic, cardiac-specific gene regulatory networks (GRNs) and transcriptional regulators during human cardiomyocyte development. Interrogating developmental trajectories reconstructed from single-cell data unexpectedly reveal divergent cardiomyocyte lineages with distinct gene programs based on developmental signaling pathways. High-throughput functional genomic screens identify key transcription factors from inferred GRNs that are functionally relevant for cardiomyocyte lineages derived from each pathway. Notably, we discover a critical heat shock transcription factor 1 (HSF1)-mediated cardiometabolic GRN controlling cardiac mitochondrial/metabolic function and cell survival, also observed in fetal human cardiomyocytes. Overall, these multi-modal genomic studies enable the systematic discovery and validation of coordinated GRNs and transcriptional regulators controlling the development of distinct human cardiomyocyte populations.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.