Scleraxis is required for the growth of adult tendons in response to mechanical loading

Gumucio, Jonathan P.; Schonk, Martin M; Kharaz, Yalda Ashraf; Comerford, Eithne; Mendias, Christopher L.

doi:10.1172/jci.insight.138295

Cited by 42 publications

(40 citation statements)

References 50 publications

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“…In addition to roles in tendon healing, Scx expression is required for appropriate tendon development and growth processes ( Murchison et al, 2007 ; Gumucio et al, 2020 ). However, the role of Scx+ cells during post-natal growth and adult homeostasis have not been evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Scx has been utilized to examine tendon biology and development ( Murchison et al, 2007 ; Pryce et al, 2009 ; Huang et al, 2019 ), healing and regeneration ( Sakabe et al, 2018 ; Howell et al, 2017 ; Best and Loiselle, 2019 ; Dyment et al, 2014 ), differentiation ( Bavin et al, 2017 ; Chen et al, 2012 ; Alberton et al, 2012 ; Nichols et al, 2018a ), and mechano-transduction ( Maeda et al, 2011 ; Nichols et al, 2018b ). Functionally, Scx expression can drive matrix production and remodeling ( Sakabe et al, 2018 ; Leéjard et al, 2007 ; Levay et al, 2008 ), epithelial-to-mesenchymal transition ( Al-Hattab et al, 2018 ), development of force-transmitting tendons ( Murchison et al, 2007 ), tendon growth ( Gumucio et al, 2020 ), and effect focal adhesion morphology ( Nichols et al, 2018b ). Despite the effort to understand the functions of Scx as a transcription factor, the function and requirement of Scx -lineage (Scx Lin ) cells in tendon repair, post-natal growth, and homeostasis has not been defined.…”

Section: Introductionmentioning

confidence: 99%

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Scleraxis-lineage cell depletion improves tendon healing and disrupts adult tendon homeostasis

Best

Korcari

Mora

et al. 2021

eLife

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Despite the requirement for Scleraxis-lineage (ScxLin) cells during tendon development, the function of ScxLin cells during adult tendon repair, post-natal growth, and adult homeostasis have not been defined. Therefore, we inducibly depleted ScxLin cells (ScxLinDTR) prior to tendon injury and repair surgery and hypothesized that ScxLinDTR mice would exhibit functionally deficient healing compared to wild-type littermates. Surprisingly, depletion of ScxLin cells resulted in increased biomechanical properties without impairments in gliding function at 28 days post-repair, indicative of regeneration. RNA sequencing of day 28 post-repair tendons highlighted differences in matrix-related genes, cell motility, cytoskeletal organization, and metabolism. We also utilized ScxLinDTR mice to define the effects on post-natal tendon growth and adult tendon homeostasis and discovered that adult ScxLin cell depletion resulted in altered tendon collagen fibril diameter, density, and dispersion. Collectively, these findings enhance our fundamental understanding of tendon cell localization, function, and fate during healing, growth, and homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scleraxis-lineage cell depletion improves tendon healing and disrupts adult tendon homeostasis

Best

Korcari

Mora

et al. 2021

eLife

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Despite the requirement for Scleraxis-lineage (ScxLin) cells during tendon development, the function of ScxLin cells during adult tendon repair, post-natal growth, and adult homeostasis have not been defined. Therefore, we inducibly depleted ScxLin cells (ScxLinDTR) prior to tendon injury and repair surgery and hypothesized that ScxLinDTR mice would exhibit functionally deficient healing compared to wild-type littermates. Surprisingly, depletion of ScxLin cells resulted in increased biomechanical properties without impairments in gliding function at 28 days post-repair, indicative of regeneration. RNA sequencing of day 28 post-repair tendons highlighted differences in matrix-related genes, cell motility, cytoskeletal organization, and metabolism. We also utilized ScxLinDTR mice to define the effects on post-natal tendon growth and adult tendon homeostasis and discovered that adult ScxLin cell depletion resulted in altered tendon collagen fibril diameter, density, and dispersion. Collectively, these findings enhance our fundamental understanding of tendon cell localization, function, and fate during healing, growth, and homeostasis.

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“…In addition to roles in tendon healing, Scx expression is required for appropriate tendon development and growth processes 8,23 . However, the role of Scx+ cells during post-natal growth and adult homeostasis have not been evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Previous work has established the importance of Scx expression in tendon development 8 , growth 23 , and healing 11 , but few studies have considered the direct contributions of Scx Lin tendon cells to these process. In the present study we examined the function of Scx Lin tendon cells during adult flexor tendon healing and made the surprising discovery that Scx Lin cell depletion significantly enhanced biomechanical properties by day 28 post-repair.…”

Section: Discussionmentioning

confidence: 99%

“…Scx has been utilized to examine tendon biology and development 8–10 , healing and regeneration 4,11–13 , differentiation 14–17 , and mechano-transduction 18,19 . Functionally, Scx expression can drive matrix production and remodeling 11,20,21 , epithelial-to-mesenchymal transition 22 , development of force-transmitting tendons 8 , tendon growth 23 , and effect focal adhesion morphology 19 . Despite the effort to understand the functions of Scx as a transcription factor, the function and requirement of Scx -lineage (Scx Lin ) cells in tendon repair, post-natal growth and homeostasis has not been defined.…”

Section: Introductionmentioning

confidence: 99%

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Scleraxis-Lineage Cell Depletion Improves Tendon Healing and Disrupts Adult Tendon Homeostasis

Best

Korcari

Mora

et al. 2020

Preprint

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Despite the requirement for Scleraxis-lineage (Scx Lin ) cells during tendon development, the function of Scx Lin cells during adult tendon repair, post-natal growth, and adult homeostasis have not been defined. Therefore, we crossed Scx-Cre and Diphtheria Toxin Receptor (DTR) mouse models to inducibly deplete Scx Lin cells prior to acute flexor tendon injury and repair (ScxLin DTR ) and hypothesized that ScxLin DTR mice would exhibit worse healing than wildtype littermates. Surprisingly, depletion of Scx Lin cells resulted in increased biomechanical properties without detriments to tendon gliding function at 28 days post-repair, indicative of regeneration. These improvements in biomechanical properties correspond to increased αSMA+ myofibroblasts in ScxLin DTR repairs, indicating that increased myofibroblast-mediated matrix remodeling may be responsible for accelerated recovery of tensile strength. Furthermore, we have defined the relative timing of Scx Lin cell localization relative to collagen deposition in bridging tissue of the repair and demonstrated a predominance of non-Scx Lin cells in the early bridging tissue, consistent with lack of bridging tissue disruption in ScxLin DTR repairs. Lastly, we utilized ScxLin DTR mice to assess effects of tendon cell depletion on post-natal tendon growth and adult tendon homeostasis. Collectively, these findings enhance our understanding of tendon cell localization, function, and fate during healing, growth, and homeostasis.3 Introduction:Despite the significant efforts toward improving tendon healing and regeneration, the specific cellular contributions during tendon healing have not been extensively characterized(1). While many studies have examined the potential of using various stem cell populations to promote healing, originating from both tendon intrinsic(2) and extrinsic sources(3), little focus has been directed toward defining the functions and therapeutic potential of tendon cells during tendon healing following an acute injury. Tendon cells are increasingly being recognized as a heterogenous population of cells where many, but not all, express the gene Scleraxis (Scx)(4-6).Understanding the localization and function of tendon cell subpopulations during healing could be instrumental in discovering why tendon heals using scar-mediated processes, resulting in poor patient outcomes, and could be used to develop pro-regenerative approaches to improve healing.Scx, a basic helix-loop-helix transcription factor, is currently the most well-characterized marker that the field possesses to study tendon (7). Scx has been utilized to examine tendon biology and development(8-10), healing and regeneration(4, 11-13), differentiation(14-17), and mechano-transduction (18,19). Functionally, Scx expression has previously been shown to drive matrix production and remodeling (11,20,21), epithelial-tomesenchymal transition(22), development of force-transmitting tendons(8), and effect focal adhesion morphology (19). Despite the effort to understand the functions of Scx as a transcr...

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Stem Cell‐Based Therapies and Tissue Engineering Innovations for Tendinopathy: A Comprehensive Review of Current Strategies and Future Directions

Augustin,

Jeong,

Kim

et al. 2024

Advanced Therapeutics

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Tendon diseases commonly lead to physical disability, exerting a profound impact on the routine of affected patients. These conditions respond poorly to existing treatments, presenting a substantial challenge for orthopedic scientists. Research into clinical translational therapy has yet to yield highly versatile interventions capable of effectively addressing tendon diseases, including tendinopathy. Stem cell‐based therapies have emerged as a promising avenue for modifying the biological milieu through the secretion of regenerative and immunomodulatory factors. In the current review, we provide an overview of the intricate tendon microenvironment, encompassing various tendon stem progenitor cells within distinct tendon sublocations, gene regulation and pathways pertinent to tendon development, and the pathology of tendon diseases. Subsequently, we discuss the advantages of stem cell‐based therapies that utilize distinct types of autologous and allogeneic stem cells for tendon regeneration at the translational level. Moreover, this review outlines the challenges, gaps, and future innovations to propose a consolidated stem cell‐based therapy to treat tendinopathy. Finally, we discuss regenerative soluble therapies, insoluble bio‐active therapies, along with insoluble bio‐active therapies, and implantable three‐dimensional scaffolds for tendon tissue engineering, thereby presenting a pathway toward enhanced tissue regeneration and engineering.This article is protected by copyright. All rights reserved

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Scleraxis is required for the growth of adult tendons in response to mechanical loading

Cited by 42 publications

References 50 publications

Scleraxis-lineage cell depletion improves tendon healing and disrupts adult tendon homeostasis

Scleraxis-lineage cell depletion improves tendon healing and disrupts adult tendon homeostasis

Scleraxis-Lineage Cell Depletion Improves Tendon Healing and Disrupts Adult Tendon Homeostasis

Stem Cell‐Based Therapies and Tissue Engineering Innovations for Tendinopathy: A Comprehensive Review of Current Strategies and Future Directions

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