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MALADAPTIVE IMMUNE-FIBROTIC AXIS DRIVES IMPAIRED LONG BONE REGENERATION UNDER MECHANICAL INSTABILITY

ABSTRACT: Delayed and non-healing fractures, affecting 5–10% of cases, are associated with prolonged disability and diminished quality of life. Although acute inflammation is required to initiate repair, persistent mechanical instability can sustain maladaptive immune and fibrotic responses that impede regeneration. Existing animal models do not adequately recapitulate mechanical instability, the principal driver of hypertrophic nonunion in clinical settings, thereby limiting translational relevance. In this study, we developed a murine model of delayed fracture healing using tunable intramedullary fixation to impose controlled interfragmentary strain. High-strain conditions (low-stiffness nail, 15-30% strain) produced enlarged calluses characterized by delayed ossification, increased fibrotic tissue (2.9-fold, p = 0.0099), and reduced biomechanical integrity (1.6-fold decrease in stiffness, p = 0.024) relative to low-strain controls (high-stiffness nail, <5% strain). Spatial transcriptomic analysis identified persistent fibrotic niches in high-strain calluses enriched with fibroblast-associated genes (e.g., Pdgfrb, Lgals3) and dysregulated macrophage-fibroblast signaling (Spp1, Mmp9). These findings identify mechanical instability as a driver of pathological immune-stromal interactions and establish a preclinical platform for investigating mechanobiology-informed therapeutic strategies. This work supports a conceptual framework in which hypertrophic nonunion is understood as a disorder arising from dysregulated interactions between mechanical cues and immune responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE338404 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:In mammals, only distal amputations of the terminal digit regenerate, while more proximal ones result in non-regenerative, fibrotic scarring, underscoring the limits of our regenerative capacity. The mechanisms that direct one wound healing process over the other remain poorly understood. In this study, we investigated the role of cell-extrinsic cues, focusing upon the role of the extracellular matrix (ECM) and the bulk mechanical properties that arise from its composition. Through single-cell RNA sequencing (scRNA-seq), we showed that non-regeneration and regeneration are differentially dominated by a select few mesenchymal cell sub-types that help determine the mechanical properties of their environment by synthesizing collagen remodeling proteins and glycosaminoglycans. In the regenerating blastema, we demonstrated that osteo-lineage cells deposit copious networks of hyaluronic acid (HA) and closely associated proteins, which corresponded with soft tissue mechanical properties. Using synthetic stiffness-tunable scaffolds, we further demonstrated that fibroblast-ECM feedback mechanisms exist, in which soft mechanical cues mimicking the blastema propagate the synthesis pro-regenerative ECM. Knockdown of HA networks critically impairs regeneration, promotes fibrotic viscoelastic mechanical properties, and enhances collagen fibrillogenesis. We further showed that stiffness affects regeneration by modulating the strength of early BMP signaling. Lastly, we stabilized the deposition of HA networks in vivo using Hyaluronic Acid and Proteoglycan Link Protein 1 (HAPLN1) to partially rescue non-regenerative amputations. Altogether, we showed that through feedback mechanisms, the ECM and emergent bulk tissue mechanics mediate mesenchymal cell activity during injury repair. These findings demonstrate that modulating the ECM microenvironment may augment restorative repair and inform future therapeutic strategies to overcome deficiencies in mammalian wound healing.

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MALADAPTIVE IMMUNE-FIBROTIC AXIS DRIVES IMPAIRED LONG BONE REGENERATION UNDER MECHANICAL INSTABILITY

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