Cell non-autonomous functions of S100a4 drive fibrotic tendon healing

Author:

Ackerman Jessica E1,Nichols Anne EC1,Studentsova Valentina1,Best Katherine T1,Knapp Emma1,Loiselle Alayna E1ORCID

Affiliation:

1. Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States

Abstract

Identification of pro-regenerative approaches to improve tendon healing is critically important as the fibrotic healing response impairs physical function. In the present study we tested the hypothesis that S100a4 haploinsufficiency or inhibition of S100a4 signaling improves tendon function following acute injury and surgical repair in a murine model. We demonstrate that S100a4 drives fibrotic tendon healing primarily through a cell non-autonomous process, with S100a4 haploinsufficiency promoting regenerative tendon healing. Moreover, inhibition of S100a4 signaling via antagonism of its putative receptor, RAGE, also decreases scar formation. Mechanistically, S100a4 haploinsufficiency decreases myofibroblast and macrophage content at the site of injury, with both cell populations being key drivers of fibrotic progression. Moreover, S100a4-lineage cells become α-SMA+ myofibroblasts, via loss of S100a4 expression. Using a combination of genetic mouse models, small molecule inhibitors and in vitro studies we have defined S100a4 as a novel, promising therapeutic candidate to improve tendon function after acute injury.

Funder

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference61 articles.

1. Deletion of EP4 in S100a4-lineage cells reduces scar tissue formation during early but not later stages of tendon healing;Ackerman;Scientific Reports,2017

2. Murine flexor tendon injury and repair surgery;Ackerman;Journal of Visualized Experiments,2016

3. S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis;Arumugam;Clinical Cancer Research,2012

4. Single-stage flexor tendoplasty in the treatment of flexor tendon injuries;Aydin;Acta Orthopaedica Et Traumatologica Turcica,2004

5. Extracellular S100A4 stimulates the migration rate of astrocytic tumor cells by modifying the organization of their actin cytoskeleton;Belot;Biochimica Et Biophysica Acta (BBA) - Proteins and Proteomics,2002

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3