Tissue elasticity and viscosity modulates macrophage-fibroblast signaling in cardiac fibrosis

The National Heart, Lung, and Blood Institute (NHLBI) awarded a $231,552 Project Grant to the University of California, San Diego on September 16, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837). This research project, titled "Tissue Elasticity and Viscosity Modulates Macrophage-Fibroblast Signaling in Cardiac Fibrosis," focuses on investigating the mechanisms underlying cardiac fibrosis through the study of interactions between macrophages and fibroblasts in controlled laboratory environments. The research addresses a critical gap in understanding how mechanical properties of tissue, including elasticity and viscosity, influence immune cell and fibroblast signaling during fibrotic disease progression, with implications for conditions such as Marfan Syndrome.

The grant supports the development of advanced in vitro co-culture methodologies that provide spatial and temporal control to better replicate in vivo cardiovascular conditions, moving beyond traditional static culture methods. This work will generate scientific data and potentially novel experimental models that advance understanding of the biochemical and biophysical mechanisms driving cardiac fibrosis. The project is scheduled for completion by March 31, 2026, with performance conducted at UCSD's facility in La Jolla, California.

Abstract

Cardiac fibrosis remains a global health problem that results from highly coordinated interactions between macrophages, versatile cells of the innate immune system, and fibroblasts, cells responsible for extracellular matrix production. Initial stages of fibrosis are characterized by an acute inflammatory response that spans a period of hours-days and is followed by a healing phase which lasts days-weeks. This creates a complex microenvironment consisting of biochemical stimuli that modulates cell function resulting in the replacement of native tissue with a more elastic and less viscous scar tissue. However, while the effects of biochemical cues have been studied, traditional CO-culture methods lack spatial and temporal control to mimic the in vivo environment. For example, static culture methods, including conditioned media transfers and direct CO-cultures, are unable fully recapitulate the close proximity of cell-cell signaling and the dynamic switch from inflammatory to healing responses in macrophage activation state to study biochemical and physical cell-cell interactions. In addition to biochemical cues, the altered mechanical environment also exposes cells to biophysical stimuli, including tissue elasticity and viscosity, that have been shown to regulate macrophage and fibroblast function independently, but the effects of mechanical stimuli in modulating macrophage-fibroblast interactions are unknown. Moreover, marfan syndrome, an autosomal dominant inherited disorder characterized by mutations to the fibrillin-1 gene, results in enhanced cellular oxidative stresses which promote pro-fibrotic cell function and alter cardiovascular tissue mechanics. However, the resulting effects on macrophages and fibroblasts as well as the role of a changing mechanical landscape in pathology are unknown. Preliminary work identified the importance of macrophage-fibroblast signaling in promoting fibrotic responses. However, several key questions remain. In this study, i hypothesize that a fibrotic environment, characterized by enhanced elasticity and reduced viscosity, promotes macrophage pro-fibrotic signaling to cardiac fibroblasts which, in turn, exacerbates cardiac fibrosis. To evaluate this hypothesis, i will develop and utilize a modular engineered cell culture system to investigate the effects of elasticity and viscosity in macrophage and fibroblast function independently and in dynamic cell-cell interactions to promote pro-fibrotic signaling (aim 1). Additionally, i will elucidate the role of elasticity and viscosity in regulating oxidative stresses to promote pro-fibrotic macrophage- fibroblast signaling in marfan syndrome (aim 2). The completion of these aims will not only provide a better understanding of material mechanics within cardiovascular disease but may also uncover molecular targets which can directly influence macrophage-fibroblast signaling and the progression of cardiovascular fibrosis.