Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells

Best, Katherine T.; Loiselle, Alayna E.

doi:10.1096/fj.201900130rr

Cited by 65 publications

(136 citation statements)

References 32 publications

(40 reference statements)

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“…At days 14 and 21, Scx Lin+ cells have organized into a cellular bridge spanning the scar tissue between the tendon stubs (Fig. 2A), similar to what was seen with Scx Ai9 mice using the flexor tendon repair model( 17 ). Virtually all αSMA+ myofibroblasts present at the healing tendon are Scx Lin+ and p-p65+ and days 14 (Fig.…”

Section: Resultssupporting

confidence: 58%

“…1C). We have previously shown that myofibroblasts, a contractile cell type that can contribute to both proper healing and pathologic tissue fibrosis( 3, 16 ), are present at the healing tendon( 17, 18 ). Co-immunofluorescence between the myofibroblast marker αSMA and p-p65 demonstrated that myofibroblasts activated canonical NF-κB signaling at both day 14 and 28 post-repair (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that most Scx -expressing tendon cells do not differentiate into αSMA+ myofibroblasts( 17 ). However, the myofibroblast fate of Scx Lin cells has not been assessed.…”

Section: Resultsmentioning

confidence: 99%

“…However, the myofibroblast fate of Scx Lin cells has not been assessed. While Scx Ai9 mice label all cells actively expressing Scx at the time of TAM injection (nearly 70% of tendon cells( 17 )), Scx Lin mice label all cells derived from the Scx lineage. The majority of tendon cells are Scx Lin+ in uninjured mouse flexor tendon (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We investigated these effects via gliding testing, tensile mechanical testing, histology, immunofluorescence, and western blot. Sample size and statistical methods were determined from previous studies and used to inform the experimental design of this work( 13, 17, 18, 28 ) in order to determine significant differences in experimental outcomes. Samples for gliding and biomechanical testing, histology and immunofluorescence, and western blotting were randomized, and blinding occurred during analysis when possible.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Tendon Cell Deletion of IKKβ/NF-κB Drives Functionally Deficient Tendon Healing and Altered Cell Survival Signaling In Vivo

Best

Knapp

Ketonis

et al. 2020

Preprint

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Acute tendon injuries are characterized by excessive matrix deposition that impedes regeneration and disrupts functional improvements. Inflammation is postulated to drive pathologic scar tissue formation, with nuclear factor kappa B (NF-κB) signaling emerging as a candidate pathway in this process. However, characterization of the spatial and temporal activation of canonical NFκ B signaling during tendon healing in vivo, including identification of the cell populations activating NF-κB, is currently unexplored. Therefore, we aimed to determine which cell populations activate canonical NF-κB signaling following flexor tendon repair with the goal of delineating cell-specific functions of NF-κB signaling during scar mediated tendon healing.Immunofluorescence revealed that both tendon cells and myofibroblasts exhibit prolonged activation of canonical NF-κB signaling into the remodeling phase of healing. Using cremediated knockout of the canonical NF-κB kinase (IKKβ), we discovered that suppression of canonical NF-κB signaling in Scleraxis-lineage cells increased myofibroblast content and scar tissue formation. Interestingly, Scleraxis-lineage specific knockout of IKKβ increased the incidence of apoptosis, suggesting that canonical NF-κB signaling may be mediating cell survival during tendon healing. These findings suggest indispensable roles for canonical NF-κB signaling during flexor tendon healing. 4 Introduction:

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Section: Resultssupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Tendon Cell Deletion of IKKβ/NF-κB Drives Functionally Deficient Tendon Healing and Altered Cell Survival Signaling In Vivo

Best

Knapp

Ketonis

et al. 2020

Preprint

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Physical and Soluble Cues Enhance Tendon Progenitor Cell Invasion into Injectable Synthetic Hydrogels

Kent

Said

Busch

et al. 2022

Adv Funct Materials

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Synthetic hydrogels represent an exciting avenue in the field of regenerative biomaterials given their injectability, orthogonally tunable mechanical properties, and potential for modular inclusion of cellular cues. Separately, recent advances in soluble factor release technology have facilitated control over the soluble milieu in cell microenvironments via tunable microparticles. A composite hydrogel incorporating both of these components can robustly mediate tendon healing following a single injection. Here, a synthetic hydrogel system with encapsulated electrospun fiber segments and a novel microgel‐based soluble factor delivery system achieves precise control over topographical and soluble features of an engineered microenvironment, respectively. It is demonstrated that three‐dimensional migration of tendon progenitor cells can be enhanced via combined mechanical, topographical, and microparticle‐delivered soluble cues in both a tendon progenitor cell spheroid model and an ex vivo murine Achilles tendon model. These results indicate that fiber reinforced hydrogels can drive the recruitment of endogenous progenitor cells relevant to the regeneration of tendon and, likely, a broad range of connective tissues.

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Engineered Microenvironmental Cues from Fiber‐Reinforced Hydrogel Composites Drive Tenogenesis and Aligned Collagen Deposition

Kent,

Jewett,

Buck

et al. 2024

Adv Healthcare Materials

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Effective tendon regeneration following injury is contingent on appropriate differentiation of recruited cells and deposition of mature, aligned, collagenous extracellular matrix that can withstand the extreme mechanical demands placed on the tissue. As such, myriad biomaterial approaches have been explored to provide biochemical and physical cues that encourage tenogenesis and template aligned matrix deposition in lieu of dysfunctional scar tissue formation. Fiber‐reinforced hydrogels present an ideal biomaterial system toward this end given their transdermal injectability, tunable stiffness over a range amenable to tenogenic differentiation of progenitors, and capacity for modular inclusion of biochemical cues. Here, tunable and modular, fiber‐reinforced, synthetic hydrogels are employed to elucidate salient microenvironmental determinants of tenogenesis and aligned collagen deposition by tendon progenitor cells. Transforming growth factor β3 drives a cell fate switch toward pro‐regenerative or pro‐fibrotic phenotypes, which can be biased toward the former by culture in softer microenvironments or inhibition of the RhoA/ROCK activity. Furthermore, studies demonstrate that topographical anisotropy in fiber‐reinforced hydrogels critically mediates the alignment of de novo collagen fibrils, reflecting native tendon architecture. These findings inform the design of cell‐free, injectable, synthetic hydrogels for tendon tissue regeneration and, likely, that of a range of load‐bearing connective tissues.This article is protected by copyright. All rights reserved

show abstract

Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells

Cited by 65 publications

References 32 publications

Tendon Cell Deletion of IKKβ/NF-κB Drives Functionally Deficient Tendon Healing and Altered Cell Survival Signaling In Vivo

Tendon Cell Deletion of IKKβ/NF-κB Drives Functionally Deficient Tendon Healing and Altered Cell Survival Signaling In Vivo

Physical and Soluble Cues Enhance Tendon Progenitor Cell Invasion into Injectable Synthetic Hydrogels

Engineered Microenvironmental Cues from Fiber‐Reinforced Hydrogel Composites Drive Tenogenesis and Aligned Collagen Deposition

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