Biology subjects

Silverman, A. A.

Publications and source records attributed to Silverman, A. A..

3 recordsLinked to original sources

bioRxiv2026

Mechano-activated synovial cells instigate OA-like disease progression in the absence of joint injury

While altered tissue mechanics and cellular mechanoactivation accompany osteoarthritis, whether dysregulated mechanotransduction can initiate joint disease remains unclear. Here, we used intra-articular delivery of cell-penetrating TAT-Cre recombinase to locally perturb the actomyosin-Hippo mechanotransduction axis in mice. Deletion of Lats1/2, the negative regulators of the mechanosensitive transcriptional coactivators YAP and TAZ, induced sustained joint hyperalgesia, altered gait, synovial hyperplasia and fibrosis, vascular remodeling, and articular cartilage degeneration in the absence of a destabilizing injury. Single-cell transcriptomics revealed the emergence of Cthrc1+ matrix-remodeling fibroblasts and accumulation of Mrc1+Trem2+ macrophages during this pathological process. Histological analyses showed persistent contractile stromal remodeling and an early macrophage response that partially subsided over four weeks. Conversely, local deletion of Myh9/10, encoding the force-generating heavy chains of non-muscle myosin II, reduced hyperalgesia, synovial lining hyperplasia, alpha-SMA+ cell accumulation, and macrophage infiltration during post-traumatic osteoarthritis (PTOA) pathogenesis. However, this intervention did not detectably reduce cartilage degeneration at eight weeks. These findings establish synovial mechanotransduction as a causal driver of joint disease via immune-stromal remodeling and pain development. In addition, partial suppression of contractility separates symptomatic from structural outcomes in PTOA. Synovial mechanotransduction therefore represents a target for modulating pathological stromal-immune remodeling and joint pain.

pathology↗

bioRxiv2021

Mechanical Causation of Biological Structure: Productive Pulls Produce Persistent Filaments in a Human Fibroblast Model of Matrix Development

The principal mechanisms driving the synthesis and organization of durable animal structure have been the subject of intense investigation for decades. Here, we present evidence that mechanical strains can direct the formation of extracellular matrix (ECM) filaments via a mechanochemical cascade. This process is driven by cooperative cell contractions ("pulls") that organize and precipitate structure via strain-induced polymer assembly. In an in vitro model of ECM synthesis, we use high-resolution optical microscopy to observe the kinematics of cell motion during their growth to confluency and identified cell-to-cell pulls that result in the production of persistent ECM filaments. Using live-cell confocal imaging, we confirmed that these pulls can directly cause the formation of fibronectin filaments that then bind collagen, producing persistent structures aligned with the direction of the pull. The finding suggests a new model for initial durable structure formation in animals based on local cell contraction, extensional strain and polymer mechanochemistry. The results have important implications for ECM development, growth and life-threatening pathologies of the ECM such as fibrosis.

developmental biology↗

bioRxiv2021

Development and Validation of Fluorescently Labeled, Functional Type I Collagen Molecules

While de novo collagen fibril formation is well-studied, there are few investigations into the growth and remodeling of extant fibrils, where molecular collagen incorporation into and erosion from the fibril surface must delicately balance during fibril growth and remodeling. Observing molecule/fibril interactions is difficult, requiring the tracking of molecular dynamics while, at the same time, minimizing the effect of the observation on fibril structure and assembly. To address the observation-interference problem, exogenous collagen molecules are tagged with small fluorophores and the fibrillogenesis kinetics of labeled collagen molecules as well as the structure and network morphology of assembled fibrils are quantified for the first time. While excessive labeling significantly disturbs fibrillogenesis kinetics and network morphology of assembled fibrils, adding less than ~1.2 labels preserves them. Applications of the functional, labeled collagen probe are demonstrated in both cellular and acellular systems. The functional, labelled collagen associates strongly with native fibrils and when added to an in vitro model of corneal stromal development, is endocytosed rapidly by cells and is translocated into synthesized matrix networks within 24 hours.

molecular biology↗