Event

 

Abstract: Fibrosis, defined as the excessive accumulation of extracellular matrix following acute and/or chronic tissue injury, is both a consequence and a driver of disease across virtually all solid organs. Despite its broad impact on human health, effective antifibrotic therapies remain limited, particularly in tissues such as the heart which has very limited regenerative capacity. Longstanding biological and technical bottlenecks in the field include: (i) the lack of fibroblast-specific, druggable targets and delivery strategies, and (ii) an underappreciated positive feedback loop in which a stiffened scar-like microenvironment further promotes fibroblast activation and transdifferentiation into matrix-producing myofibroblasts—even after the initial profibrotic signals (e.g., inflammatory cytokines) have subsided. In this seminar, I will present a new conceptual and therapeutic framework that addresses both of these challenges simultaneously. This approach is based on the identification of a cardiac stroma–enriched mechanosensor gene, SRC, that can be targeted pharmacologically to coerce myofibroblasts into perceiving a stiff, profibrotic environment as soft, in vivo. Across multiple experimental scales—from iPSC-derived cells and engineered tissues to animal models of heart failure—fibroblast-selective inhibition of matrix mechanosensing induces coordinated transcriptomic, morphological, and metabolic reprogramming toward a quiescent state, acting in concert with soluble regulators of the TGFβ pathway. I will discuss the mechanistic basis by which integrated biochemical and mechanical cues within the fibrotic niche govern fibroblast state plasticity. The seminar will then highlight the synergistic impact of this dual-targeting strategy in suppressing fibrosis and improving contractile function in failing hearts, establishing the first proof-of-concept 'mechanotherapy' for treating cardiovascular fibrosis. Finally, I will outline how this framework may (or may not) be extended to diverse forms of heart disease and, more broadly, to fibrosis-associated pathological conditions in other organ systems.

 

Bio: Sangkyun (Sang) Cho, PhD is an Assistant Professor in the Department of Chemical & Biomolecular Engineering at Johns Hopkins University with a secondary appointment in Biomedical Engineering, and a core faculty member of the Institute for NanoBioTechnology (INBT) and the Center for Microphysiological Systems (CMPS). His research integrates organoid/materials engineering, cardiovascular systems biology, and regenerative medicine to develop precision 'mechanotherapies' for cardiac fibrosis and heart failure. Dr. Cho received his PhD in Chemical & Biomolecular Engineering from the University of Pennsylvania, where he trained with Dennis Discher on nuclear mechanosensing in cardiac development and aging. He completed postdoctoral training with Joseph Wu at Stanford University School of Medicine, leading projects on iPSC-based cardiac models, single-cell and spatial omics, and fibrosis biology. He is the recipient of multiple honors, including the NIH F32 Ruth L. Kirschstein NRSA Postdoctoral Fellowship, the American Heart Association (AHA) Career Development Award, and the NIH K99/R00 Pathway to Independence Award.