Coupled Transcriptomic and ECM-Mechanical Remodeling Reveal Mechanotransductive Pathways in Spinal Cord Injury

Abstract

Spinal cord injury (SCI) leads to the formation of a chronic scar composed of glial and fibrotic components that severely restrict neural regeneration and functional recovery. While the scar composition has been widely studied, the spatiotemporal evolution of tissue mechanics and the role it plays in regulating the post-injury responses remain poorly understood. Here we present an integrated mechanobiological and multi-omics analysis of spinal cord remodeling following a severe thoracic contusion injury. Using nanoindentation and viscoelasticity measurements taken via atomic force microscopy (AFM), we demonstrate that SCI induces a dynamic mechanical response characterized by rapid tissue softening during the acute phase reaching a minimum at one-month post-injury, followed by progressive stiffening associated with chronic scar maturation at six months. Bulk RNA sequencing reveals that early mechanical softening coincides with strong activation of inflammatory and matrix-degrading pathways whereas chronic stiffening correlates with upregulation of collagen synthesis, extracellular matrix (ECM) organization and fibrotic remodeling pathways. Concurrently, mechanotransduction regulators exhibit temporally coordinated activation, indicating that cells dynamically sense and respond to evolving mechanical cues. Viscoelastic analysis further shows that chronic scar tissue exhibited increased stiffness and prolonged relaxation dynamics, reflecting dense collagen deposition and proteoglycan accumulation that reinforces a mechanically restrictive microenvironment. Together, these findings establish that the post-injury scar represents a dynamic mechanobiological system in which the evolving tissue mechanics, viscoelasticity and mechanotransduction collectively regulate ECM remodeling, resulting in regenerative failure. This study provides a comprehensive mechanobiological framework for SCI progression and highlights the opportunities for mechanically informed therapeutic strategies aimed at modulating scar mechanics to promote tissue repair. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/736147v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@543cc4org.highwire.dtl.DTLVardef@6185c6org.highwire.dtl.DTLVardef@95c3ceorg.highwire.dtl.DTLVardef@6a12ea_HPS_FORMAT_FIGEXP M_FIG C_FIG