Defining the spatial-molecular map of fibrotic tendon healing and the drivers of Scleraxis-lineage cell fate and function

Ackerman, Jessica E.; Best, Katherine T.; Muscat, Samantha; Pritchett, Elizabeth M.; Nichols, Anne E. C.; Wu, Chia‐Lung; Loiselle, Alayna E.

doi:10.1016/j.celrep.2022.111706

Cited by 17 publications

(28 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The number of Ki67+ GLAST Ai9 cells in the epitenon peaked at D7 (77.2 ± 2.6%) before declining through D28 (D10: 56.1 ± 5.0%, D14: 14.6% ± 3.7, D21: 7.2 ± 2.3%, D28: 2.8 ± 1.1%). These proliferation dynamics are in contrast to tenocyte proliferation which peaks between D12 and D14 in this model 22 , and supports previous suggestions that the epitenon is the primary early responder population following acute tendon injury.…”

Section: Resultssupporting

confidence: 90%

“…In addition to GLAST Ai9 ; Scx-GFP+ cells in the organized bridging tissue, we observed a persistent band of GLAST Ai9 ; Scx-GFP- cells in a peripheral capsule surrounding the injury site in the region primarily associated with the formation of fibrotic, peritendinous adhesions 22 from D14 on ( Fig. 3A ; orange arrows).…”

Section: Resultsmentioning

confidence: 92%

“…Mice then underwent complete transection and repair of the flexor digitorum longus (FDL) tendon in the hind paw as previously described. 22, 24, 50, 63–65 Briefly, mice were anesthetized with Ketamine (100mg/kg) and Xylazine (10mg/kg) and sustained-release buprenorphine (ZooPharm™; 0.5-1.0 mg/kg) was applied subcutaneously for post-operative pain management. To reduce chances of rupture at the repair site, the FDL tendon was first transected at the myotendinous junction (MTJ) and the skin was closed with non-resorbable 5-0 suture (#668G Ethilon, Ethicon Inc., Bridgewater, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Epitenon-derived cells comprise a distinct progenitor population that contributes to both tendon fibrosis and regeneration following acute injury

Nichols

Wagner

Ketonis

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Flexor tendon injuries are common and heal poorly owing to both the deposition of function- limiting peritendinous scar tissue and insufficient healing of the tendon itself. Therapeutic options are limited due to a lack of understanding of the cell populations that contribute to these processes. Here, we identified a bi-fated progenitor cell population that originates from the epitenon and goes on to contribute to both peritendinous fibrosis and regenerative tendon healing following acute tendon injury. Using a combination of genetic lineage tracing and single cell RNA-sequencing (scRNA-seq), we profiled the behavior and contributions of each cell fate to the healing process in a spatio-temporal manner. Branched pseudotime trajectory analysis identified distinct transcription factors responsible for regulation of each fate. Finally, integrated scRNA-seq analysis of mouse healing with human peritendinous scar tissue revealed remarkable transcriptional similarity between mouse epitenon- derived cells and fibroblasts present in human peritendinous scar tissue, which was further validated by immunofluorescent staining for conserved markers. Combined, these results clearly identify the epitenon as the cellular origin of an important progenitor cell population that could be leveraged to improve tendon healing.

show abstract

Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Epitenon-derived cells comprise a distinct progenitor population that contributes to both tendon fibrosis and regeneration following acute injury

Nichols

Wagner

Ketonis

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Unbiased Gene Discovery Methodsmentioning

confidence: 99%

“…There are several current platforms, including 10X Genomics Visium Spatial gene expression, Merscope (MerFISH; Vizgen), and GeoMx/CosMx (Nanostring), each with differing strengths (reviewed in Williams et al 48 ). Published and preprint studies in human and mouse have utilized the 10X Visium platform to show spatial distributions of cell types, including in mouse, cell cluster localization over healing stages 49 and in humans, specific fibroblast cell subtypes (MKX vs. PDGFRA) or myotendinous junction cells. 44,46,50 Complementing RNA-seq analyses are studies examining potential upstream regulatory regions using either ATAC-seq or ChIP-seq, which can expand our understanding of potential upstream transcription factors through motif-analysis of bound regions and of downstream target pathways.…”

Section: Multiomicsmentioning

confidence: 99%

Current and emerging technologies for defining and validating tendon cell fate

Huang

Galloway

2023

Journal Orthopaedic Research

View full text Add to dashboard Cite

The tendon field has been flourishing in recent years with the advent of new tools and model systems. The recent ORS 2022 Tendon Section Conference brought together researchers from diverse disciplines and backgrounds, showcasing studies in biomechanics and tissue engineering to cell and developmental biology and using models from zebrafish and mouse to humans. This perspective aims to summarize progress in tendon research as it pertains to understanding and studying tendon cell fate. The successful integration of new technologies and approaches have the potential to further propel tendon research into a new renaissance of discovery. However, there are also limitations with the current methodologies that are important to consider when tackling research questions. Altogether, we will highlight recent advances and technologies and propose new avenues to explore tendon biology.

show abstract

Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how)

Little

Amadio

Awad

et al. 2023

Journal Orthopaedic Research

View full text Add to dashboard Cite

Several tendon and ligament animal models were presented at the 2022 Orthopaedic Research Society Tendon Section Conference held at the University of Pennsylvania, May 5‐7, 2022. A key objective of the breakout sessions at this meeting was to develop guidelines for the field, including for preclinical tendon and ligament animal models. This review summarizes the perspectives of experts for eight surgical small and large animal models of rotator cuff tear, flexor tendon transection, anterior cruciate ligament tear, and Achilles tendon injury using the framework: “Why, Who, What, Where, When, and How” (5W1H). A notable conclusion is that the perfect tendon model does not exist; there is no single gold standard animal model that represents the totality of tendon and ligament disease. Each model has advantages and disadvantages and should be carefully considered in light of the specific research question. There are also circumstances when an animal model is not the best approach. The wide variety of tendon and ligament pathologies necessitates choices between small and large animal models, different anatomic sites, and a range of factors associated with each model during the planning phase. Attendees agreed on some guiding principles including: providing clear justification for the model selected, providing animal model details at publication, encouraging sharing of protocols and expertise, improving training of research personnel, and considering greater collaboration with veterinarians. A clear path for translating from animal models to clinical practice was also considered as a critical next step for accelerating progress in the tendon and ligament field.This article is protected by copyright. All rights reserved.

show abstract

Defining the spatial-molecular map of fibrotic tendon healing and the drivers of Scleraxis-lineage cell fate and function

Cited by 17 publications

References 68 publications

Epitenon-derived cells comprise a distinct progenitor population that contributes to both tendon fibrosis and regeneration following acute injury

Epitenon-derived cells comprise a distinct progenitor population that contributes to both tendon fibrosis and regeneration following acute injury

Current and emerging technologies for defining and validating tendon cell fate

Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how)

Contact Info

Product

Resources

About