FGF7 promotes load-bearing tendon regeneration and suppresses fibrosis

1. Liu, M., López de Juan Abad, B. & Cheng, K. Cardiac fibrosis: myofibroblast-mediated pathological regulation and drug delivery strategies. Adv. Drug Deliv. Rev. 173, 504–19 (2021).

   Google Scholar 

2. Hernandez-Gea, V. & Friedman, S. L. Pathogenesis of liver fibrosis. Annu. Rev. Pathol. 6, 425–56 (2011).

   Google Scholar 

3. Wijsenbeek, M. & Cottin, V. Spectrum of fibrotic lung diseases. N. Engl. J. Med. 383, 958–68 (2020).

   Google Scholar 

4. Harvey, T., Flamenco, S. & Fan, C. M. A Tppp3(+)Pdgfra(+) tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis. Nat. Cell Biol. 21, 1490–503 (2019).

   Google Scholar 

5. Karsdal, M. A. et al. The good and the bad collagens of fibrosis—their role in signaling and organ function. Adv. Drug Deliv. Rev. 121, 43–56 (2017).

   Google Scholar 

6. Yelin, E., Weinstein, S. & King, T. The burden of musculoskeletal diseases in the United States. Semin. Arthritis Rheum. 46, 259–60 (2016).

   Google Scholar 

7. Havis, E. et al. TGFβ and FGF promote tendon progenitor fate and act downstream of muscle contraction to regulate tendon differentiation during chick limb development. Development 143, 3839–51 (2016).

   Google Scholar 

8. Havis, E. et al. Transcriptomic analysis of mouse limb tendon cells during development. Development 141, 3683–96 (2014).

   Google Scholar 

9. Liu, C. et al. Disrupted tenogenesis in masseter as a potential cause of micrognathia. Int. J. Oral. Sci. 14, 50 (2022).

   Google Scholar 

10. Rana, R. et al. Impaired 1,25-dihydroxyvitamin D3 action underlies enthesopathy development in the Hyp mouse model of X-linked hypophosphatemia. JCI Insight 8, e163259 (2023).

    Google Scholar 

11. Tokunaga, T. et al. FGF-2 stimulates the growth of tenogenic progenitor cells to facilitate the generation of tenomodulin-positive tenocytes in a rat rotator cuff healing model. Am. J. Sports Med. 43, 2411–22 (2015).

    Google Scholar 

12. Liu, S. et al. Tendon healing and anti-adhesion properties of electrospun fibrous membranes containing bFGF loaded nanoparticles. Biomaterials 34, 4690–701 (2013).

    Google Scholar 

13. Livingston, M. J. et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy 19, 256–77 (2023).

    Google Scholar 

14. Kim, Y. S., Lee, J. S., Jeong, M. Y., Jang, J. W. & Kim, M. S. Recombinant human fibroblast growth factor 7 obtained from stable Chinese hamster ovary cells enhances wound healing. Biotechnol. J. 19, e2300596 (2024).

    Google Scholar 

15. Mongiat, M. et al. The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7. J. Biol. Chem. 275, 7095–100 (2000).

    Google Scholar 

16. Hayes, A. J., Farrugia, B. L., Biose, I. J., Bix, G. J. & Melrose, J. Perlecan, a multi-functional, cell-instructive, matrix-stabilizing proteoglycan with roles in tissue development has relevance to connective tissue repair and regeneration. Front. Cell Dev. Biol. 10, 856261 (2022).

    Google Scholar 

17. Geervliet, E., Terstappen, L. & Bansal, R. Hepatocyte survival and proliferation by fibroblast growth factor 7 attenuates liver inflammation, and fibrogenesis during acute liver injury via paracrine mechanisms. Biomed. Pharmacother. 167, 115612 (2023).

    Google Scholar 

18. Zhang, H. et al. Cell-subpopulation alteration and FGF7 activation regulate the function of tendon stem/progenitor cells in 3D microenvironment revealed by single-cell analysis. Biomaterials 280, 121238 (2022).

    Google Scholar 

19. Ren, Y. et al. Gene expression of Postn and FGF7 in canine chordae tendineae and their effects on flexor tenocyte biology. J. Orthop. Res. 42, 961–72 (2024).

    Google Scholar 

20. He, S. et al. Spatial-temporal proliferation of hepatocytes during pregnancy revealed by genetic lineage tracing. Cell Stem Cell 30, 1549–58.e5 (2023).

    Google Scholar 

21. He, L. et al. Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair. Science 371, eabc4346 (2021).

    Google Scholar 

22. Liu, X., Weng, W., He, L. & Zhou, B. Genetic recording of in vivo cell proliferation by ProTracer. Nat. Protoc. 18, 2349–73 (2023).

    Google Scholar 

23. Fan, C. et al. A Cd9(+)Cd271(+) stem/progenitor population and the SHP2 pathway contribute to neonatal-to-adult switching that regulates tendon maturation. Cell Rep. 39, 110762 (2022).

    Google Scholar 

24. Mienaltowski, M. J., Adams, S. M. & Birk, D. E. Regional differences in stem cell/progenitor cell populations from the mouse achilles tendon. Tissue Eng. Part A 19, 199–210 (2013).

    Google Scholar 

25. Chen, W. et al. Lysyl oxidase (LOX) family members: rationale and their potential as therapeutic targets for liver fibrosis. Hepatology 72, 729–41 (2020).

    Google Scholar 

26. Tzanidis, A. et al. Direct actions of urotensin II on the heart: implications for cardiac fibrosis and hypertrophy. Circ. Res. 93, 246–53 (2003).

    Google Scholar 

27. Mölleken, C. et al. Direct-acting antivirals-based therapy decreases hepatic fibrosis serum biomarker microfibrillar-associated protein 4 in hepatitis C patients. Clin. Mol. Hepatol. 25, 42–51 (2019).

    Google Scholar 

28. Liu, Q. et al. DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding. Nat. Aging 4, 664–80 (2024).

    Google Scholar 

29. Grinstein, M. et al. A distinct transition from cell growth to physiological homeostasis in the tendon. Elife 8, e48689 (2019).

    Google Scholar 

30. Zhang, C. et al. Histone deacetylase inhibitor treated cell sheet from mouse tendon stem/progenitor cells promotes tendon repair. Biomaterials 172, 66–82 (2018).

    Google Scholar 

31. Russo, V. et al. Scaffold-mediated immunoengineering as innovative strategy for tendon regeneration. Cells 11, 266 (2022).

    Google Scholar 

32. Schweitzer, R., Zelzer, E. & Volk, T. Connecting muscles to tendons: tendons and musculoskeletal development in flies and vertebrates. Development 137, 2807–17 (2010).

    Google Scholar 

33. Brent, A. E., Schweitzer, R. & Tabin, C. J. A somitic compartment of tendon progenitors. Cell 113, 235–48 (2003).

    Google Scholar 

34. Edom-Vovard, F., Schuler, B., Bonnin, M. A., Teillet, M. A. & Duprez, D. Fgf4 positively regulates scleraxis and tenascin expression in chick limb tendons. Dev. Biol. 247, 351–66 (2002).

    Google Scholar 

35. Brown, J. P., Finley, V. G. & Kuo, C. K. Embryonic mechanical and soluble cues regulate tendon progenitor cell gene expression as a function of developmental stage and anatomical origin. J. Biomech. 47, 214–22 (2014).

    Google Scholar 

36. Eloy-Trinquet, S., Wang, H., Edom-Vovard, F. & Duprez, D. Fgf signaling components are associated with muscles and tendons during limb development. Dev. Dyn. 238, 1195–206 (2009).

    Google Scholar 

37. Li, K., Zhang, X., Wang, D., Tuan, R. S. & Ker, D. Synergistic effects of growth factor-based serum-free medium and tendon-like substrate topography on tenogenesis of mesenchymal stem cells. Biomater. Adv. 146, 213316 (2023).

    Google Scholar 

38. Li, B. et al. Early cellular responses of BMSCs genetically modified with bFGF/BMP2 co-cultured with ligament fibroblasts in a three-dimensional model in vitro. Int. J. Mol. Med. 38, 1578–86 (2016).

    Google Scholar 

39. Zinkle, A. & Mohammadi, M. Structural biology of the FGF7 subfamily. Front. Genet. 10, 102 (2019).

    Google Scholar 

40. Wang, T. et al. Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries. Sci. Transl. Med. 13, eabe5738 (2021). pii.

    Google Scholar 

41. Yin, Z. et al. The regulation of tendon stem cell differentiation by the alignment of nanofibers. Biomaterials 31, 2163–75 (2010).

    Google Scholar 

42. Zhang, Y. et al. 3D printing of chemical-empowered tendon stem/progenitor cells for functional tissue repair. Biomaterials 271, 120722 (2021).

    Google Scholar 

43. Chen, T. et al. The genome sequence archive family: toward explosive data growth and diverse data types. Genomics Proteom. Bioinforma. 19, 578–83 (2021).

    Google Scholar 

44. CNCB-NGDC Members and Partners. Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2022. Nucleic Acids Res. 50, D27–D28 (2022).

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Author notes

1. These authors contributed equally: Ruifu Lin, Junchao Luo, Hong Zhang.

Authors and Affiliations

1. Department of Orthopedic Surgery of Sir Run Run Shaw Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China

   Ruifu Lin, Ruojin Yan, Zetao Wang, Yang Fei, Tianshun Fang, Hongwei Ouyang & Zi Yin

2. Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, PR China

   Ruifu Lin, Chunmei Fan, Yue Hu, Ruojin Yan, Zetao Wang, Tianxi Huang, Tianshun Fang, Hongwei Ouyang, Xiao Chen & Zi Yin

3. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, PR China

   Ruifu Lin, Zetao Wang, Tianshun Fang, Xiao Chen & Zi Yin

4. Department of Sports Medicine & Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

   Junchao Luo, Yang Fei, Chenqi Tang, Weiliang Shen & Xiao Chen

5. Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China

   Hong Zhang

6. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, PR China

   Chunmei Fan

7. Institute of Translational Medicine, Zhejiang University, Hangzhou, China

   Sunbin Ling

8. State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China

   Xiao Chen

9. Institute of Cell Biology Zhejiang University, Hangzhou, China

   Zi Yin

Contributions

The study was conceived by R.L., H.Z., J.L., H.O., X.C., and Z.Y. The experiments were designed by R.L., Y.H., and T.H. Figures were prepared by J.L., T.H., R.L., and Z.W. Manuscript writing was carried out by R.L. and Z.Y. Animal experiments were assisted by Z.W., R.L., F.Y., S.L., and T.F. Clinical samples were collected by F.Y., J.L., W.S., and C.T. Bioinformatics analyses were performed by J.L., R.L., R.Y., and C.F. Molecular experiments were conducted by R.L. and J.L. Figure optimization was done by Y.Z. and X.C.

Corresponding authors

Correspondence to Xiao Chen or Zi Yin.

Competing interests

The authors declare no competing interests.

Peer review information

Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. A peer review file is available.

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