TGFβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration

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Abstract

Tendon injuries are common with poor healing potential. The paucity of therapies for tendon injuries is due to our limited understanding of the cells and molecular pathways that drive tendon regeneration. Using a mouse model of neonatal tendon regeneration, we identified TGFβ signaling as a major molecular pathway that drives neonatal tendon regeneration. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGFβ-dependent and TGFβ-independent mechanisms underlying tendon regeneration. Importantly, functional recovery depended on canonical TGFβ signaling and loss of function is due to impaired tenogenic cell recruitment from both Scleraxis-lineage and non-Scleraxis-lineage sources. We show that TGFβ signaling is directly required in neonatal tenocytes for recruitment and that TGFβ ligand is positively regulated in tendons. Collectively, these results show a functional role for canonical TGFβ signaling in tendon regeneration and offer new insights toward the divergent cellular activities that distinguish regenerative vs fibrotic healing.

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All data analyzed in this study are included in the manuscript.

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Deepak A Kaji

Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Kristen L Howell

Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Zerina Balic

Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Dirk Hubmacher

Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Alice H Huang

Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, United States

For correspondence
alice.huang@mssm.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5037-6829

Funding

National Institutes of Health (R01AR069537)

Alice H Huang

National Institutes of Health (F31AR073626)

Deepak A Kaji

National Institutes of Health (R01AR070748)

Dirk Hubmacher

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 and all procedures approved by the institutional animal care and use committee (IACUC) at Mount Sinai (IACUC-2014-0031).

Copyright

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.