Despite the requirement for Scleraxis-lineage (ScxLin) cells during tendon development, function of ScxLin adult repair, post-natal growth, and homeostasis have not been defined. Therefore, we inducibly depleted (ScxLinDTR) prior to injury repair surgery hypothesized that ScxLinDTR mice would exhibit functionally deficient healing compared wild-type littermates. Surprisingly, depletion resulted in increased biomechanical properties without impairments gliding at 28 days post-repair,...

Satisfactory healing following acute tendon injury is marred by fibrosis. Despite the high frequency of injuries and poor outcomes, there are no pharmacological therapies in use to enhance process. Moreover, systemic treatments demonstrate homing, limiting beneficial effects potential therapeutics. To address this unmet need, we leveraged our existing spatial transcriptomics dataset identified an area enriched for expression

Identification of pro-regenerative approaches to improve tendon healing is critically important as the fibrotic response impairs physical function. In present study we tested hypothesis that S100a4 haploinsufficiency or inhibition signaling improves function following acute injury and surgical repair in a murine model. We demonstrate drives primarily through cell non-autonomous process, with promoting regenerative healing. Moreover, via antagonism its putative receptor, RAGE, also decreases...

Although inflammation is necessary during the early phases of tissue repair, persistent contributes to fibrosis. Acute tendon injuries often heal through a fibrotic mechanism, which impedes regeneration and functional recovery. Because mediated by nuclear factor κB (NF-κB) signaling implicated in this process, we examined spatial, temporal, cell type-specific activation profile canonical NF-κB healing. was maintained all healing mice, including remodeling phase, tenocytes myofibroblasts from...

Aged tendons have disrupted homeostasis, increased injury risk, and impaired healing capacity. Understanding mechanisms of homeostatic disruption is crucial for developing therapeutics to retain tendon health through the lifespan. Here, we developed a novel model accelerated extracellular matrix (ECM) aging via depletion Scleraxis-lineage cells in young mice (Scx-DTR). Scx-DTR recapitulates many aspects including comparable declines cellularity, alterations ECM structure, organization,...

Abstract Satisfactory outcomes after acute tendon injuries are hampered by a fibrotic healing response. As such, modulation of extracellular matrix deposition and remodeling represents an important intervention point to improve healing. During fibrosis, is deposited remodeled activated fibroblasts and/or myofibroblasts. Recent work has demonstrated that Ogerin, positive allosteric modulator the orphan proton‐sensing GPCR, GPR68, can modulate fibroblast ↔ myofibroblast dynamics in multiple...

Tendinopathies are common and difficult to resolve due the formation of scar tissue that reduces mechanical integrity tissue, leading frequent reinjury. Tenocytes respond both excessive loading unloading by producing pro-inflammatory mediators, suggesting these cells actively involved in development tendon degeneration. The transcription factor scleraxis (Scx) is required for force-transmitting during mechanically stimulated tenogenesis stem cells, but its function adult tenocytes less...

ABSTRACT Adipose‐derived stromal vascular fraction (SVF) is a heterogeneous population of cells that yields homogeneous plastic‐adherent adipose tissue‐derived (ASC) when culture‐expanded. SVF and ASC have been used clinically to improve tendon healing, yet their mechanism action not fully elucidated. The objective this study was investigate the potential for act as trophic mediators healing. Flexor digitorum superficialis tendons tissue were harvested from adult horses obtain SVF, ASC,...

Abstract During tendon healing, macrophages are thought to be a key mediator of scar tissue formation, which prevents successful functional restoration the tendon. However, critical for healing as they aid in wound debridement, extracellular matrix deposition, and promote fibroblast proliferation. Recent work has sought better define multi‐faceted functions using depletion studies, while other studies have identified resident macrophage population. To begin delineate tendon‐resident versus...

Flexor tendon injuries are common and heal poorly owing to both the deposition of function- limiting peritendinous scar tissue insufficient healing itself. Therapeutic options limited due a lack understanding cell populations that contribute these processes. Here, we identified bi-fated progenitor population originates from epitenon goes on fibrosis regenerative following acute injury. Using combination genetic lineage tracing single RNA-sequencing (scRNA-seq), profiled behavior...

Efforts to generate tissue-engineered anterior cruciate ligament replacements are limited by a lack of methods derive mature cells. Viral overexpression the tendon/ligament marker scleraxis (Scx) can drive cell differentiation; however, use viral vectors hampers translation clinical use. In this study, C3H10T1/2 cells were transiently transfected with expression containing full-length murine Scx cDNA and cultured in three-dimensional collagen hydrogels under static or cyclic strain for up 14...

Tendon injuries are common and heal poorly, due in part to a lack of understanding fundamental tendon cell biology. A major impediment the study cells is absence robust, well-characterized vitro models. Unlike other tissue systems, current models do not account for how differences isolation methodology may affect activation state or presence various subpopulations. The objective this was characterize methods behavior, fate, lineage composition cultures. isolated by explant exhibited reduced...

Abstract Aged tendons have disrupted homeostasis, increased injury risk, and impaired healing capacity. Understanding mechanisms of homeostatic disruption is crucial for developing therapeutics to retain tendon health through the lifespan. Here, we developed a novel model accelerated extracellular matrix (ECM) aging via depletion Scleraxis-lineage (Scx Lin ) cells in young mice (DTR). DTR recapitulates many aspects including comparable declines cellularity, alterations ECM structure,...

Abstract The use of tamoxifen‐inducible models Cre recombinase in the tendon field is rapidly expanding, resulting an enhanced understanding homeostasis and healing. However, effects tamoxifen on are not well‐defined, which particularly problematic given that can have both profibrotic antifibrotic a tissue‐specific manner. Therefore, present study, we examined healing male female C57Bl/6J mice. Tamoxifen‐treated mice were compared to corn oil (vehicle)‐treated In “washout” treatment regimen,...

Tendon regeneration following acute injury is marred by a fibrotic healing response that prevents complete functional recovery. Despite the high frequency of tendon injuries and poor outcomes, including deficits elevated risk re-injury, there are currently no pharmacological therapies in clinical use to enhance process. Several promising pharmacotherapies have been identified; however, systemic treatments lack specificity, resulting biodistribution perhaps explaining largely limited...

Achilles tendinopathy is a debilitating condition affecting the entire spectrum of society and that increases risk tendon rupture. Effective therapies remain elusive, as anti-inflammatory drugs surgical interventions show poor long-term outcomes. Eccentric loading muscle-tendon unit an effective physical therapy for treatment symptomatic human tendinopathy. Here, we introduce novel mouse model hindlimb muscle designed to achieve tissue-targeted therapeutic exercise. This includes application...

Successful tendon healing requires sufficient deposition and remodeling of new extracellular matrix at the site injury, with this process mediating in part through fibroblast activation via communication macrophages. Moreover, resolution clearance or reversion activated cells, chronic interactions persistent macrophages impairing facilitating conversion to fibrotic healing. As such, modulation macrophage environment represents an important translational target improve process. Circulating...

Successful tendon healing requires sufficient deposition and remodeling of new extracellular matrix at the site injury, with this process mediating in part through fibroblast activation via communication macrophages. Moreover, resolution clearance or reversion activated cells, chronic interactions persistent macrophages impairing facilitating conversion to fibrotic healing. As such, modulation macrophage environment represents an important translational target improve process. Circulating...