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Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice.
J Biol Chem. 2018 04 20; 293(16):5766-5780.JB

Abstract

Tendon is a dense connective tissue that transmits high mechanical forces from skeletal muscle to bone. The transcription factor scleraxis (Scx) is a highly specific marker of both precursor and mature tendon cells (tenocytes). Mice lacking scx exhibit a specific and virtually complete loss of tendons during development. However, the functional contribution of Scx to wound healing in adult tendon has not yet been fully characterized. Here, using ScxGFP-tracking and loss-of-function systems, we show in an adult mouse model of Achilles tendon injury that paratenon cells, representing a stem cell antigen-1 (Sca-1)-positive and Scx-negative progenitor subpopulation, display Scx induction, migrate to the wound site, and produce extracellular matrix (ECM) to bridge the defect, whereas resident tenocytes exhibit a delayed response. Scx induction in the progenitors is initiated by transforming growth factor β (TGF-β) signaling. scx-deficient mice had migration of Sca-1-positive progenitor cell to the lesion site but impaired ECM assembly to bridge the defect. Mechanistically, scx-null progenitors displayed higher chondrogenic potential with up-regulation of SRY-box 9 (Sox9) coactivator PPAR-γ coactivator-1α (PGC-1α) in vitro, and knock-in analysis revealed that forced expression of full-length scx significantly inhibited Sox9 expression. Accordingly, scx-null wounds formed cartilage-like tissues that developed ectopic ossification. Our findings indicate a critical role of Scx in a progenitor-cell lineage in wound healing of adult mouse tendon. These progenitor cells could represent targets in strategies to facilitate tendon repair. We propose that this lineage-regulatory mechanism in tissue progenitors could apply to a broader set of tissues or biological systems in the body.

Authors+Show Affiliations

From the Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom. Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.From the Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom. Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.From the Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom.Research Division, Shriners Hospital for Children, Portland, Oregon 97239, and.Department of Biochemistry, Faculty of Medicine, Oita University, Oita 879-5593, Japan.From the Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom, sakait@liverpool.ac.uk. Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29507095

Citation

Sakabe, Tomoya, et al. "Transcription Factor Scleraxis Vitally Contributes to Progenitor Lineage Direction in Wound Healing of Adult Tendon in Mice." The Journal of Biological Chemistry, vol. 293, no. 16, 2018, pp. 5766-5780.
Sakabe T, Sakai K, Maeda T, et al. Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice. J Biol Chem. 2018;293(16):5766-5780.
Sakabe, T., Sakai, K., Maeda, T., Sunaga, A., Furuta, N., Schweitzer, R., Sasaki, T., & Sakai, T. (2018). Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice. The Journal of Biological Chemistry, 293(16), 5766-5780. https://doi.org/10.1074/jbc.RA118.001987
Sakabe T, et al. Transcription Factor Scleraxis Vitally Contributes to Progenitor Lineage Direction in Wound Healing of Adult Tendon in Mice. J Biol Chem. 2018 04 20;293(16):5766-5780. PubMed PMID: 29507095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice. AU - Sakabe,Tomoya, AU - Sakai,Keiko, AU - Maeda,Toru, AU - Sunaga,Ataru, AU - Furuta,Nao, AU - Schweitzer,Ronen, AU - Sasaki,Takako, AU - Sakai,Takao, Y1 - 2018/03/05/ PY - 2018/01/18/received PY - 2018/02/16/revised PY - 2018/3/7/pubmed PY - 2019/1/9/medline PY - 2018/3/7/entrez KW - cell biology KW - conditional knockout KW - extracellular matrix KW - mouse genetics KW - scleraxis KW - tendon KW - tissue progenitor cells KW - transforming growth factor β (TGF-β) KW - wound healing SP - 5766 EP - 5780 JF - The Journal of biological chemistry JO - J Biol Chem VL - 293 IS - 16 N2 - Tendon is a dense connective tissue that transmits high mechanical forces from skeletal muscle to bone. The transcription factor scleraxis (Scx) is a highly specific marker of both precursor and mature tendon cells (tenocytes). Mice lacking scx exhibit a specific and virtually complete loss of tendons during development. However, the functional contribution of Scx to wound healing in adult tendon has not yet been fully characterized. Here, using ScxGFP-tracking and loss-of-function systems, we show in an adult mouse model of Achilles tendon injury that paratenon cells, representing a stem cell antigen-1 (Sca-1)-positive and Scx-negative progenitor subpopulation, display Scx induction, migrate to the wound site, and produce extracellular matrix (ECM) to bridge the defect, whereas resident tenocytes exhibit a delayed response. Scx induction in the progenitors is initiated by transforming growth factor β (TGF-β) signaling. scx-deficient mice had migration of Sca-1-positive progenitor cell to the lesion site but impaired ECM assembly to bridge the defect. Mechanistically, scx-null progenitors displayed higher chondrogenic potential with up-regulation of SRY-box 9 (Sox9) coactivator PPAR-γ coactivator-1α (PGC-1α) in vitro, and knock-in analysis revealed that forced expression of full-length scx significantly inhibited Sox9 expression. Accordingly, scx-null wounds formed cartilage-like tissues that developed ectopic ossification. Our findings indicate a critical role of Scx in a progenitor-cell lineage in wound healing of adult mouse tendon. These progenitor cells could represent targets in strategies to facilitate tendon repair. We propose that this lineage-regulatory mechanism in tissue progenitors could apply to a broader set of tissues or biological systems in the body. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29507095/Transcription_factor_scleraxis_vitally_contributes_to_progenitor_lineage_direction_in_wound_healing_of_adult_tendon_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)40932-9 DB - PRIME DP - Unbound Medicine ER -