Biology subjects

Kahan, S.

Publications and source records attributed to Kahan, S..

3 recordsLinked to original sources

bioRxiv2026

Wnt/β-catenin signaling regulates fibrotic atrophy of intra-articular adipose tissue in post-traumatic osteoarthritis

Synovial joints like the knee are home to adipose tissue depots whose anatomy and functions are closely intertwined with that of other intra-articular soft tissues such as synovium, underscoring the growing understanding that joints are multi-tissue organs. Traumatic joint injury and the onset of osteoarthritis (OA) dramatically remodel the intra-articular adipose niche, marked by infiltration of fibrotic tissue postulated to underpin OA-associated joint stiffness and pain, yet we know very little about the disease-associated dynamics of joint adipose remodeling nor the mechanisms driving these phenomena. Here, we employed 2D histomorphometry and spatial transcriptomics, alongside 3D osmium tetroxide-enhanced micro-computed tomography to comprehensively define the spatiotemporal, structural, and transcriptional rewiring of joint adipose tissue in a non-invasive mouse model of post-traumatic osteoarthritis (PTOA). These revealed marked loss of intra-articular adiposity accompanied by expansion of fibroblast-rich, collagen-dense tissue with pro-fibrotic hallmarks and Wnt/{beta}-catenin-enriched gene programs. Joint adipose exhibited a distinct transcriptional signature compared to subcutaneous white adipose tissue, pointing to unique, depot-specific functions. Stromal cells isolated from PTOA joints had heightened baseline expression of fibrotic and Wnt pathway genes and exhibited impaired de novo adipogenesis, in contrast to cells derived from healthy joints. In accordance with the destabilized biomechanics of PTOA joints, in vitro modeling demonstrated that prolonged, injurious loading and perturbed Wnt/{beta}-catenin signaling were convergent anti-adipogenic cues that suppressed lipid droplet formation and adipogenic gene induction, while promoting markers of fibrosis in joint-derived stromal cells. Complementary gain-of-function studies using ex vivo joint adipose explants and in vivo joint injections demonstrated that chronic Wnt/{beta}-catenin activation, as seen in OA joints, is sufficient to diminish the intra-articular adipogenic program and shift adipose to a more fibrotic phenotype, independent of joint injury. Collectively, these findings establish a multi-modal framework for quantifying joint adipose atrophy and implicate aberrant Wnt/{beta}-catenin signaling and pathological mechanical loading as key factors impairing de novo adipogenesis and driving fibrotic remodeling of intra-articular adipose tissue in PTOA.

cell biology↗

bioRxiv2022

Modeling the biomechanics of cells on microcarriers in a stirred-tank bioreactor An ABM-CFD coupling approach

Highly productive and efficient growth of biomass in bioreactors is an essential bioprocess outcome in many industrial applications. In the nascent cultivated meat industry, large-scale biomass creation will be critical given the size of demand in the conventional meat and seafood sectors. However, there are many challenges that must be overcome before cultivated meat and seafood become commercially viable including cost reductions of cell culture media, bioprocess design innovation and optimization, and scaling up in the longer term. Computational modelling and simulation can help to address many of these challenges, and can be a far cheaper and faster alternative to performing physical experiments. Computer modelling can also help researchers pinpoint system interactions that matter, and guide researchers to identify those parameters that should be changed in later designs for eventual optimization. In this work, a computational model that combines agent-based modeling and computational fluid dynamics was developed to study biomass growth as a function of the operative conditions of stirred-tank bioreactors. The focus was to analyze how the mechanical stress induced by rotor speed can influence the growth of cells attached to spherical microcarriers. The computer simulation results reproduced observations from physical experiments that high rotor speeds reduce cell growth rates and induce cell death under the high mechanical stresses induced at these stir speeds. Moreover, the results suggest that modeling both cell death and cell quiescence are required to recapitulate these observations from physical experiments. These simulation outcomes are the first step towards more comprehensive models that, in combination with experimental observations, will improve our knowledge of biomass production in bioreactors for cultivated meat and other industries.

bioinformatics↗

bioRxiv2019

An Integrated Multiscale, Multicellular Skin Model

Skin is our primary barrier to the outside world, protecting us from physical, biological and chemical threats. Developing innovative products that preserve and improve skin barrier function requires a thorough understanding of the mechanisms underlying barrier response to topical applications. In many fields, computer simulations already facilitate understanding, thus accelerating innovation. Simulations of software models allow scientists to test hypothesized mechanisms by comparing predicted results to physical observations. They also enable virtual product optimization, without physical experiments, once mechanisms have been validated. The physical accessibility and abundant knowledge of skin structure makes it a prime candidate for computational modeling. In this article, we describe a computational multiscale multicellular skin model used to simulate growth and response of the epidermal barrier. The model integrates several modeling styles and mathematical frameworks including ordinary differential equations, partial differential equations, discrete agent-based modeling and discrete element methods. Specifically, to capture cell biology and physical transport, we combined four distinct sub-models from existing literature. We also implemented methods for elastic biomechanics. Our software implementation of the model is compatible with the high-performance computing simulation platform Biocellion. The integrated model recapitulates barrier formation, homeostasis and response to environmental, chemical and mechanical perturbation. This work exemplifies methodology for integrating models of vastly different styles. The methodology enables us to effectively build on existing knowledge and produce "whole-system" tissue models capable of displaying emergent properties. It also illustrates the inherent technical difficulties associated with the mounting complexity of describing biological systems at high fidelity. Among the challenges are validation of the science, the mathematical representations approximating the science and the software implementing these representations. Responsibility for a discrepancy observed between in silico and in vitro results may as easily lie at one of these three levels as at another, demanding that any sustainable modeling endeavor engage expertise from biology, mathematics and computing.

systems biology↗