A latent Axin2+/Scx+ progenitor pool is the central organizer of tendon healing
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<sup>+</sup>/Axin2<sup>+</sup> population in mouse and human tendons that initiates healing and is a major functional contributor to repair. Axin2<sup>+</sup> cells express stem cell markers, expand in vitro, and have multilineage differentiation potential. Following tendon injury, Axin2<sup>+</sup>-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<sup>+</sup> identity. Specific loss of Wnt secretion in Axin2<sup>+</sup> or Scx<sup>+</sup> cells disrupts their ability to respond to injury, severely compromising healing. Our work highlights an unusual paradigm, wherein specialized Axin2<sup>+</sup>/Scx<sup>+</sup> cells rely on self-regulation to maintain their identity as key organizers of tissue healing.
Authors
- David Mooney (ORCID: https://orcid.org/0000-0001-6299-1194)
- Ken Zou (ORCID: https://orcid.org/0000-0003-0825-8041)
- Steffany Villaseñor
- Terence D. Capellini (ORCID: https://orcid.org/0000-0003-3842-8478)
- Jayaraj Rajagopal (ORCID: https://orcid.org/0000-0002-4122-177X)
- Daniel T. Montoro (ORCID: https://orcid.org/0000-0002-6222-2149)
- Stephanie Tsai (ORCID: https://orcid.org/0000-0001-7549-3418)
- Benjamin R. Freedman (ORCID: https://orcid.org/0000-0001-9406-773X)
- Miho J. Tanaka (ORCID: https://orcid.org/0000-0001-6489-3803)
- Moshe Sade-Feldman (ORCID: https://orcid.org/0000-0002-0022-0287)
- Heather L. Dingwall (ORCID: https://orcid.org/0000-0003-2377-9777)
- Mor Grinstein (ORCID: https://orcid.org/0000-0001-7166-5593)
- Jenna L. Galloway (ORCID: https://orcid.org/0000-0003-3792-3290)
Institutions
- Broad Institute (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Center for Cancer Research (US)
- Center for Systems Biology (US)
- Harvard Stem Cell Institute (US)
Publication Details
- Journal
- npj Regenerative Medicine
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1038/s41536-024-00370-2
- Citations
- 12
- Primary Topic
- Tendon Structure and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.26
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- American Federation for Aging Research
- Helen Hay Whitney Foundation
- Human Frontier Science Program
- Harvard Stem Cell Institute
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases