Biology subjects

Astrab, L. R.

Publications and source records attributed to Astrab, L. R..

5 recordsLinked to original sources

bioRxiv2026

An agent-based model suggests how senescent cell behavior and matrix mechanics drive pulmonary fibrosis in aged mice

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease of aging, driven by dysregulated fibroblast activation and accompanied by collagen accumulation in the lung interstitium, resulting in tissue stiffening. While the accumulation of senescent cells has been increasingly implicated in IPF pathogenesis, understanding the reciprocal dynamics of senescent fibroblast levels and evolving tissue mechanics is difficult to achieve with experimental approaches alone. To address this limitation, we developed an agent-based model (ABM) of fibroblast activation in the lung that couples cell behavior to the dynamic mechanical changes accompanying fibrosis. This model was parameterized entirely from experimental data in young mice to enable robust validation and then adapted to fit aged mouse biology for additional validation. Both young and aged models accurately reflected changes in collagen accumulation and stiffness burden of experimental systems. We then incorporated senescent cell behavior into the aged model to investigate how senescent cell burden influences fibrosis progression and how cell-cell interactions drive senescent cell accumulation. These simulations identified a unique role for juxtacrine-mediated contact between non-senescent and senescent fibroblasts in expanding the total senescent cell burden. Our ABM also revealed that the timing of immune-mediated senescent cell clearance critically regulates fibrotic outcomes. Together, this ABM provides useful insights into how the interrelated dynamics of tissue mechanics and senescent fibroblasts drive fibrosis progression.

bioengineering↗

bioRxiv2025

Cadherin-11 integrates Piezo1 and interleukin-6 signaling to promote fibroblast activation

Persistent fibroblast activation drives tissue fibrosis, yet how mechanical and inflammatory cues are integrated to promote this aberrant behavior remains unclear. Using a hyaluronic acid (HA)-based hydrogel platform to model normal and fibrotic lung mechanics, we examine the roles of Piezo1 and cadherin-11 (CDH11), both implicated in M2 macrophage-fibroblast crosstalk during pulmonary fibrosis progression, in interleukin (IL)-6-mediated fibroblast activation. While both Piezo1 and CDH11 expression increase in activated fibroblasts, blocking IL-6 signaling decreases CDH11, but not Piezo1, expression. Instead, Piezo1 activity promotes nuclear accumulation of the calcium-dependent transcription factor NFAT1. While Piezo1 inhibition moderately reduces CDH11 expression, it does not prevent fibroblast activation as measured by spreading and type I collagen expression, whereas CDH11 knockout suppresses fibroblast activation metrics, reduces Piezo1 expression, and decreases IL-6 secretion in both fibroblast only and fibroblast-M2 macrophage co-cultures. Furthermore, CDH11 levels increase in parallel with progressive fibroblast activation, highlighting its role in promoting this pro-fibrotic phenotype. Together, these findings underscore a previously unrecognized signaling axis in which CDH11 serves as a key mediator of sustained fibroblast activation, coordinating mechanical and inflammatory cues, and highlight CDH11 as a potential therapeutic target in pulmonary fibrosis.

bioengineering↗

bioRxiv2025

Lung tissue viscoelasticity is preserved with bleomycin-induced fibrosis in mice

In pulmonary fibrosis, excessive scar tissue accumulates in the alveolar interstitial space, impairing gas exchange and compromising lung function. This fibrotic remodeling results in tissue stiffening, but more complex lung mechanical properties critical to tissue function, such as viscoelasticity and stress relaxation, remain poorly defined. To address this gap, we use the bleomycin aged mouse model to characterize both bulk and spatially-resolved viscoelastic mechanical properties of normal and fibrotic lungs. Our analysis reveals that while bleomycin-induced fibrosis leads to heterogeneously increased lung stiffness, viscoelasticity as measured by tan delta (ratio of loss to storage modulus) and stress relaxation timescales remains remarkably consistent as a function of both age and bleomycin treatment. This unexpected preservation of viscoelasticity despite fibrotic stiffening highlights a previously underappreciated mechanical phenotype of fibrotic lungs. To model these distinct mechanical features in vitro, we utilize a hyaluronic acid-based hydrogel system that largely recapitulates the viscoelastic mechanical properties observed in both normal and fibrotic lungs. These findings provide new insight into the mechanical consequences of fibrosis and establish a tunable in vitro hydrogel platform mimicking key tissue viscoelastic properties.

bioengineering↗

bioRxiv2024

Direct M2 macrophage co-culture overrides viscoelastic hydrogel mechanics to promote fibroblast activation

Fibroblast activation drives fibrotic diseases such as pulmonary fibrosis. However, the complex interplay of how tissue mechanics and macrophage signals combine to influence fibroblast activation is not well understood. Here, we use hyaluronic acid hydrogels as a tunable cell culture system to mimic lung tissue stiffness and viscoelasticity. We applied this platform to investigate the influence of macrophage signaling on fibroblast activation. Fibroblasts cultured on stiff (50 kPa) hydrogels mimicking fibrotic tissue exhibit increased activation as measured by spreading as well as type I collagen and cadherin-11 expression compared to fibroblasts cultured on soft (1 kPa) viscoelastic hydrogels mimicking normal tissue. These trends were unchanged in fibroblasts cultured with macrophage-conditioned media. However, fibroblasts directly co-cultured with M2 macrophages show increased activation, even on soft viscoelastic hydrogels that normally suppress activation. Inhibition of interleukin 6 (IL6) signaling does not change activation in fibroblast-only cultures but ameliorates the pro-fibrotic effects of M2 macrophage co-culture. These results underscore the ability of direct M2 macrophage co-culture to override hydrogel viscoelasticity to promote fibroblast activation in an IL6-dependent manner. This work also highlights the utility of using hydrogels to deconstruct complex tissue microenvironments to better understand the interplay between microenvironmental mechanical and cellular cues.

bioengineering↗

bioRxiv2023

Modular multiwell viscoelastic hydrogel platform for two- and three-dimensional cell culture applications

Hydrogels have gained significant popularity as model platforms to study the reciprocal interactions between cells and their microenvironment. While hydrogel tools to probe many characteristics of the extracellular space have been developed, fabrication approaches remain challenging and time-consuming, limiting multiplexing or widespread adoption. Thus, we have developed a modular fabrication approach to generate distinct hydrogel microenvironments within 96-well plates for increased throughput of fabrication as well as integration with existing high-throughput assay technologies. This approach enables in situ hydrogel mechanical characterization and was used to generate both elastic and viscoelastic hydrogels across a range of stiffnesses. Additionally, this fabrication method enabled a 3-fold reduction in polymer and up to an 8-fold reduction in fabrication time required per hydrogel replicate. The feasibility of this platform for cell culture applications was demonstrated by measuring both population-level and single cell-level metrics via microplate reader and high-content imaging. Finally, the 96-well hydrogel array was utilized for 3D cell culture, demonstrating the ability to support high cell viability. Together, this work demonstrates a versatile and easily adoptable fabrication approach that can support the ever-expanding tool kit of hydrogel technologies for cell culture applications.

bioengineering↗