Depletion of Scleraxis-lineage cells during tendon healing transiently impairs multi-scale restoration of tendon structure during early healing
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ABSTRACT:
PROVIDER: PRJNA878813 | ENA |
REPOSITORIES: ENA
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Project description:Tendons are composed of a heterogeneous cell environment, with Scleraxis-lineage (ScxLin) cells being the predominant population. Although ScxLin cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of ScxLin cells during tendon healing, and identified that the overall ScxLin pool continuously expands up to early remodeling healing phase. To better define the function of ScxLin cells during the late proliferative phase of healing, we inducibly depleted ScxLin cells from day 14-18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of ScxLin cells in the healing tendon. At D28 post-surgery, ScxLin cell depleted tendons (DTRScxLin) had substantial impairments in structure and function, relative to WT, demonstrating the importance of ScxLin cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that ScxLin depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTRScxLin were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of ScxLin cells during tendon healing.
2022-09-13 | GSE213033 | GEO
Project description:Little is understood about the roles of tendon cells during flexor tendon healing. To better understand tendon cell functions, the Scx-Cre mouse was crossed to the DTR mouse model to facilitate scleraxis lineage cell depletion prior to acute flexor tendon injury and repair. WT (cre-) and experimental (cre+) mice underwent complete transection and repair of the flexor digitorum longus tendon. Repaired tendons were harvested at 14 and 28 days post-repair for bulk RNA-Seq analysis to examine possible mechanisms driving differential healing due to Scx lineage cell depletion.
2021-02-08 | GSE156157 | GEO
Project description:Tendons play fundamental role in the musculoskeletal system and locomotion by transferring forces generated by muscles to the skeleton. Tendon injuries can occur due to sports related incidents, as a result of trauma to overuse or during disease or ageing and are among the leading causes of musculoskeletal disability. Scleraxis is a marker of the tendon lineage and appears to be induced at the earliest stage of specification of this lineage, however little is known how scleraxis is modulating tendon growth activity. This study aimed to investigate how scleraxis modulates tendon cells activity.
2021-09-08 | PXD017944 | Pride
Project description: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 of accelerated tendon extracellular matrix (ECM) aging via depletion of Scleraxis-lineage (ScxLin) cells in young mice (DTR). DTR recapitulates many aspects of tendon aging including comparable declines in cellularity, alterations in ECM structure, organization, and composition. Single cell RNA-sequencing demonstrated a conserved decline in tenocytes associated with ECM biosynthesis in aged and DTR tendons, identifying the requirement for ScxLin cells during homeostasis. However, the remaining cells in aged and DTR tendons demonstrate functional divergence. Aged tenocytes become pro-inflammatory and lose proteostasis. In contrast, DTR tenocytes demonstrate enhanced remodeling capacity. Collectively, this study defines DTR a novel model of accelerated tendon ECM aging and identifies novel biological intervention points to maintain tendon function through the lifespan.
2023-02-03 | PXD037230 | Pride
Project description:Tendons are composed of a heterogeneous cell environment, with Scleraxis-lineage (ScxLin) cells being the predominant population. Although ScxLin cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of ScxLin cells during tendon healing, and identified that the overall ScxLin pool continuously expands up to early remodeling healing phase. To better define the function of ScxLin cells during the late proliferative phase of healing, we inducibly depleted ScxLin cells from day 14-18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of ScxLin cells in the healing tendon. At D28 post-surgery, ScxLin cell depleted tendons (DTRScxLin) had substantial impairments in structure and function, relative to WT, demonstrating the importance of ScxLin cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that ScxLin depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTRScxLin were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of ScxLin cells during tendon healing.
| S-EPMC9565440 | biostudies-literature
Project description:Spatial transcriptomic analysis of murine FDL tendons following acute injury and repair to evaluate spatiotemporal programming of tendon healing
2022-10-25 | GSE216214 | GEO
Project description:We have undertaken a screen of mouse limb tendon cells in order to identify molecular pathways involved in tendon development. Mouse limb tendon cells were isolated based on Scleraxis (Scx) expression at different stages of development: E11.5, E12.5 and E14.5 Microarray comparisons were carried out between tendon progenitor and differentiated stages. Forelimbs from E11.5, E12.5 and E14.5 Scx-GFP embryos were collected and dissociated with trypsin to obtain cell suspensions. Scx-positive tendon cells were isolated by FACS. RNA was extracted and Fragmented biotin-labelled cRNA samples were hybridized on Affymetrix Gene Chip Mouse Genome 430 2.0 arrays.
2014-01-18 | E-GEOD-54207 | biostudies-arrayexpress
Project description:We have undertaken a screen of mouse limb tendon cells in order to identify molecular pathways involved in tendon development. Mouse limb tendon cells were isolated based on Scleraxis (Scx) expression at different stages of development: E11.5, E12.5 and E14.5 Microarray comparisons were carried out between tendon progenitor and differentiated stages.
2014-01-18 | GSE54207 | GEO
Project description:We report RNA sequencing data from the plantaris tendons of adult male mice in the C57Bl/6 background that either have the scleraxis gene (Scx+) or mice in which scleraxis has been deleted using CreERT2 driven from the Rosa26 locus (Scx-). Mice in which scleraxis was deleted were created by crossing scleraxis-floxed mice with Rosa26-CreERT2 mice. Rosa26-CreERT2 mice that did not have a floxed scleraxis allele served as controls. Mice were treated with tamoxifen for 5 days to induce recombination at the scleraxis locus, and then subjected to a synergist ablation procedure in which the Achilles tendon is removed, resulting in compensatory growth of the plantaris tendon. Mice were analyzed either 7 or 14 days after synergist ablation. Control mice that did not undergo tamoxifen treatment or synergist ablation were also studied (NOC).
2020-01-31 | GSE139493 | GEO
Project description:Rotator cuff injuries result in over 500,000 surgeries performed annually, an alarmingly high number of which fail. These procedures typically involve repair of the injured tendon and removal of the subacromial bursa. However, recent identification of a resident population of mesenchymal stem cells and inflammatory responsiveness of the bursa to tendinopathy indicate an unexplored biological role of the bursa in the context of rotator cuff disease. Therefore, we aimed to understand the clinical relevance of bursa-tendon crosstalk, characterize the biologic role of the bursa within the shoulder, and test the therapeutic potential for targeting the bursa. Proteomic profiling of patient bursa and tendon samples demonstrated that the bursa is activated by tendon injury. Using a rat to model rotator cuff injury and repair, tenotomy-activated bursa protected the intact tendon adjacent to the injured tendon and maintained the morphology of the underlying bone. The bursa also promoted an early inflammatory response in the injured tendon, initiating key players in wound healing. In vivo results were supported by targeted organ culture studies of the bursa. To examine the potential to therapeutically target the bursa, dexamethasone was delivered to the bursa, prompting a shift in cellular signaling towards modulating inflammation in the healing tendon. In conclusion, contrary to current clinical practice, the bursa should be retained to the greatest extent possible and provides a new therapeutically target for improving tendon healing outcomes.
2023-07-07 | GSE235861 | GEO