Biology subjects

Celebi, L. E.

Publications and source records attributed to Celebi, L. E..

4 recordsLinked to original sources

bioRxiv2026

Doxorubicin-induced Cardiotoxicity is Propagated by Paracrine Signaling through Small Extracellular Vesicles

Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. While most of these deaths are the result of chronic heart diseases, some CVDs are induced artificially. Doxorubicin (DOX) is a chemotherapeutic that is commonly used to treat breast cancer which is one of the most common types of cancer in the United States. While DOX is an effective anti-cancer agent, over 10% of treated women show signs of acute cardiotoxicity immediately following treatment, and approximately 2% develop severe cardiotoxicity up to 10 years after the end of treatment. Despite this prevalence, the mechanism by which the onset of this cardiotoxicity occurs over time is not well understood. Here, we show that treatment of cardiac cells with DOX changes the cardiac function and the resulting paracrine signaling profile. Subsequent exposure of healthy cells to these altered paracrine agents can recapitulate the effects of direct DOX exposure in 2D and 3D in vitro models. We suggest that this is the result of an altered paracrine miRNA profile and other paracrine factors that propagate the initial disruption caused by direct DOX exposure. Plasma EV miRNA profiling of blinded patient samples revealed distinct clustering by DOX-cardiotoxicity risk, with high-risk patients exhibiting miRNA signatures similar to those from DOX-treated tissue-engineered models. Pathway analysis of the most distinguishing miRNAs linked them to cardiac homeostasis and cardiotoxicity-related mechanisms, supporting the potential of plasma EV miRNAs as noninvasive biomarkers for early risk stratification and personalized cardioprotective interventions in oncological care, and the targeting of key clusters of miRNAs to enhance both understanding of and intervention strategies for preventing the onset of DOX cardiotoxicity.

bioengineering↗

bioRxiv2025

Mitochondria Clearance Enables Macrophage-Driven Maturation of iPSC-Derived Cardiomyocyte Metabolism

Generation of functional engineered myocardial tissue remains a challenge, owing in part to lacking maturity of stem cell-derived cardiomyocytes. Current strategies to mature these cells fall short of achieving in vivo-like physiology. Macrophages, members of the innate immune system, reside in the heart and exert positive effects on cardiomyocyte function. We hypothesized that developmentally informed addition of macrophages to cardiomyocytes would improve their maturity. While some recent studies have added macrophages to stem cell-derived models of the human myocardium, these previous approaches do not replicate the early colonization of the heart. Addition of macrophages to developing cardiomyocytes 8 days after the start of differentiation significantly alters cardiomyocyte behavior. We show that macrophages drive improvements in metabolic capabilities of cardiomyocytes. Developing cardiomyocytes shed lowly polarized mitochondria, adopt a new mitochondria network architecture, and develop more active mitophagy programs after >20 days coculture with macrophages. This interaction is dependent on macrophage MerTK reception of cardiomyocyte-derived mitochondria material. These results inform our understanding of the responsibility of macrophages in the development of the myocardium, and we hope that these interactions can be leveraged to produce more physiologically relevant models of the human myocardium.

bioengineering↗

bioRxiv2025

3D Bioprinted Fat-Myocardium Model Unravels the Role of Adipocyte Hypertrophy in Atrial Dysfunction

Cardiovascular diseases (CVD) are the leading cause of mortality in individuals with obesity. Epicardial adipose tissue (EAT) dysfunction serves as a link between obesity and CVD, promoting inflammatory and metabolic alterations that increase CVD risk. While EAT normally supports cardiac health, obesity-induced adipocyte hypertrophy triggers excessive fatty acid and cytokine release, driving myocardial lipotoxicity and inflammation that impair electrophysiology and metabolism, leading to beating irregularities, insulin resistance, and heart failure. The lack of sufficient EAT in small animal models and the impracticality of using large mammals hinder insights into the effects of EAT hypertrophy on the myocardium. To address this gap, a human-derived 3D bioprinted coculture of obese adipocytes and cardiomyocytes (CMs) is developed using patient-derived adipocytes and human induced pluripotent stem cell (hiPSC)-derived atrial CMs (a-iCMs). This platform enables the investigation of both cell-cell and paracrine interactions between hypertrophic adipocytes and a-iCMs, allowing assessment of electrophysiological, structural, and proteomic changes to uncover mechanisms linking EAT hypertrophy to obesity-related atrial dysfunction. Screening of metformin, a cardioprotective drug, reveals improvement in electrophysiological function in hypertrophic adipocyte-a-iCM cultures. 3D bioprinted fat-myocardium model provides a high-throughput platform to study obesity-induced atrial dysfunction and facilitate discovery of therapies for the obese heart.

bioengineering↗

bioRxiv2025

Substrate Stiffness Modulates Fibroblast Extracellular Vesicle Secretion via Mechanotransduction Pathways

The extracellular matrix (ECM) is recognized as a key regulator of cell behavior, with its stiffness playing a crucial role in the progression of pathological conditions such as cancer and cardiovascular diseases. While extracellular vesicles (EVs) are essential mediators of intercellular communication, the influence of matrix stiffness on EV secretion remains poorly understood. This study investigates how substrate stiffness affects EV size and composition in mouse mammary and cardiac fibroblasts, the key stromal cell types in breast cancer and cardiac microenvironments. Importantly, we uncovered stiffness-tuned EV proteomic cargo, providing new insights into how mechanical cues can reprogram the signaling functions of fibroblast-derived vesicles. Our findings show that substrate stiffness significantly alters EV characteristics, with sizes increasing below stiffnesses of 20 kPa and decreasing on stiffer substrates. Mechanotransduction pathways involving p53 and thioredoxin were identified as regulators of these alterations, with thioredoxin dominating the modulation in mammary fibroblasts and p53 in cardiac fibroblasts. These results underscore the importance of ECM stiffness in modulating EV secretion and highlight candidate pathways influenced by ECM remodeling that may warrant further investigation for therapeutic relevance.

bioengineering↗