A CD26+ tendon stem progenitor cell population contributes to tendon repair and heterotopic ossification

Siwen Chen; Yingxin Lin; Hao Yang; Zihao Li; Sifang Li; Dongying Chen; Wenjun Hao; Shuai Zhang; Hua Chao; Jingyu Zhang; Jianru Wang; Zemin Li; Xiang Li; Zhongping Zhan; Hui Liu

doi:10.1038/s41467-025-56112-5

A CD26⁺ tendon stem progenitor cell population contributes to tendon repair and heterotopic ossification

Nat Commun. 2025 Jan 16;16(1):749. doi: 10.1038/s41467-025-56112-5.

Authors

Siwen Chen^#^{1

2}, Yingxin Lin^#^{3

4

5}, Hao Yang^#⁶, Zihao Li^{1

2}, Sifang Li^{1

2}, Dongying Chen⁷, Wenjun Hao^{1

2}, Shuai Zhang^{1

2}, Hua Chao^{1

2}, Jingyu Zhang^{1

2}, Jianru Wang^{1

2}, Zemin Li^{1

2}, Xiang Li^{1

2}, Zhongping Zhan⁷, Hui Liu^{8

9}

Affiliations

¹ Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangdong, PR China.
² Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangdong, PR China.
³ School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia.
⁴ Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
⁵ Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, PR China.
⁶ Pediatric Orthopaedics, Beijing Jishuitan Hospital, Peking University, Beijing, PR China.
⁷ Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong, PR China.
⁸ Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangdong, PR China. liuhui58@mail.sysu.edu.cn.
⁹ Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangdong, PR China. liuhui58@mail.sysu.edu.cn.

^# Contributed equally.

Abstract

Inadequate tendon healing and heterotopic bone formation result in substantial pain and disability, yet the specific cells responsible for tendon healing remain uncertain. Here we identify a CD26⁺ tendon stem/progenitor cells residing in peritendon, which constitutes a primitive stem cell population with self-renewal and multipotent differentiation potentials. CD26⁺ tendon stem/progenitor cells migrate into the tendon midsubstance and differentiation into tenocytes during tendon healing, while ablation of these cells led to insufficient tendon healing. Additionally, CD26⁺ tendon stem/progenitor cells contribute to heterotopic ossification and Tenascin-C-Hippo signaling is involved in this process. Targeting Tenascin-C significantly suppresses chondrogenesis of CD26⁺ tendon stem/progenitor cells and subsequent heterotopic ossification. Our findings provide insights into the identification of tendon stem/progenitor cells and illustrate the essential role of CD26⁺ tendon stem/progenitor cells in tendon healing and heterotopic bone formation.

MeSH terms

Animals
Cell Differentiation
Chondrogenesis
Dipeptidyl Peptidase 4* / genetics
Dipeptidyl Peptidase 4* / metabolism
Female
Male
Mice
Mice, Inbred C57BL
Ossification, Heterotopic* / metabolism
Ossification, Heterotopic* / pathology
Signal Transduction
Stem Cells* / cytology
Stem Cells* / metabolism
Tenascin / metabolism
Tendon Injuries* / metabolism
Tendon Injuries* / pathology
Tendons* / cytology
Tendons* / metabolism
Tendons* / pathology
Tenocytes / metabolism
Wound Healing* / physiology

Substances

Dipeptidyl Peptidase 4
Tenascin