Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype

  1. Antonion Korcari
  2. Anne EC Nichols
  3. Mark R Buckley
  4. Alayna E Loiselle  Is a corresponding author
  1. University of Rochester Medical Center, United States

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 of accelerated tendon extracellular matrix (ECM) aging via depletion of Scleraxis-lineage cells in young mice (Scx-DTR). Scx-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 Scx-DTR tendons, identifying the requirement for Scleraxis-lineage cells during homeostasis. However, the remaining cells in aged and Scx-DTR tendons demonstrate functional divergence. Aged tenocytes become pro-inflammatory and lose proteostasis. In contrast, tenocytes from Scx-DTR tendons demonstrate enhanced remodeling capacity. Collectively, this study defines Scx-DTR as a novel model of accelerated tendon ECM aging and identifies novel biological intervention points to maintain tendon function through the lifespan.

Data availability

Single cell RNA sequencing data has been deposited at Gene Expression Omnibus (GEO) (Accession # GSE214929) and are publicly available as of the date of publication. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE 38 partner repository with the dataset identifier PXD037230.

The following data sets were generated

Article and author information

Author details

  1. Antonion Korcari

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anne EC Nichols

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8754-7735
  3. Mark R Buckley

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alayna E Loiselle

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    For correspondence
    alayna_loiselle@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7548-6653

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR073169)

  • Alayna E Loiselle

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR077527)

  • Alayna E Loiselle

National Institute of Arthritis and Musculoskeletal and Skin Diseases (K99 AR080757)

  • Anne EC Nichols

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal studies were approved by the University Committee for Animal Resources (UCAR) (protocol 2014-004E)

Reviewing Editor

  1. Mei Wan, Johns Hopkins University, United States

Publication history

  1. Received: October 13, 2022
  2. Accepted: January 18, 2023
  3. Accepted Manuscript published: January 19, 2023 (version 1)

Copyright

© 2023, Korcari et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Antonion Korcari
  2. Anne EC Nichols
  3. Mark R Buckley
  4. Alayna E Loiselle
(2023)
Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype
eLife 12:e84194.
https://doi.org/10.7554/eLife.84194
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