Abstract

A tendon’s ordered extracellular matrix (ECM) is essential for transmitting force but is also highly prone to injury. How tendon cells embedded within and surrounding this dense ECM orchestrate healing is not well understood. Here, we identify a specialized quiescent Scx+/Axin2+ population in mouse and human tendons that initiates healing and is a major functional contributor to repair. Axin2+ cells express stem cell markers, expand in vitro, and have multilineage differentiation potential. Following tendon injury, Axin2+-descendants infiltrate the injury site, proliferate, and differentiate into tenocytes. Transplantation assays of Axin2-labeled cells into injured tendons reveal their dual capacity to significantly proliferate and differentiate yet retain their Axin2+ identity. Specific loss of Wnt secretion in Axin2+ or Scx+ cells disrupts their ability to respond to injury, severely compromising healing. Our work highlights an unusual paradigm, wherein specialized Axin2+/Scx+ cells rely on self-regulation to maintain their identity as key organizers of tissue healing.

Details

Title
A latent Axin2+/Scx+ progenitor pool is the central organizer of tendon healing
Author
Grinstein, Mor 1   VIAFID ORCID Logo  ; Tsai, Stephanie L. 1 ; Montoro, Daniel 2 ; Freedman, Benjamin R. 3 ; Dingwall, Heather L. 4 ; Villaseñor, Steffany 5 ; Zou, Ken 5 ; Sade-Feldman, Moshe 6 ; Tanaka, Miho J. 7   VIAFID ORCID Logo  ; Mooney, David J. 3 ; Capellini, Terence D. 8   VIAFID ORCID Logo  ; Rajagopal, Jayaraj 9   VIAFID ORCID Logo  ; Galloway, Jenna L. 1   VIAFID ORCID Logo 

1  Massachusetts General Hospital, Center for Regenerative Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Medical School, Department of Orthopedic Surgery, Massachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard Stem Cell Institute, Cambridge, USA (GRID:grid.511171.2) 
2  Massachusetts General Hospital, Center for Regenerative Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Medical School, Department of Medicine, Massachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
3  Harvard University, John A. Paulson School of Engineering and Applied Sciences, Cambridge, USA (GRID:grid.38142.3c) (ISNI:0000 0004 1936 754X); Harvard University, Wyss Institute for Biologically Inspired Engineering, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
4  Massachusetts General Hospital, Center for Regenerative Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard University, Department of Human Evolutionary Biology, Cambridge, USA (GRID:grid.38142.3c) (ISNI:0000 0004 1936 754X) 
5  Massachusetts General Hospital, Center for Regenerative Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
6  Harvard Medical School, The Center for Cancer Research, Massachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
7  Harvard Medical School, Department of Orthopedic Surgery, Massachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
8  Harvard University, Department of Human Evolutionary Biology, Cambridge, USA (GRID:grid.38142.3c) (ISNI:0000 0004 1936 754X); Broad Institute of Harvard and MIT, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
9  Massachusetts General Hospital, Center for Regenerative Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Stem Cell Institute, Cambridge, USA (GRID:grid.511171.2); Harvard Medical School, Department of Medicine, Massachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
Pages
30
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20573995
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41536-024-00370-2
ProQuest document ID
3117781458
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.