1.
Webster, K. E., Feller, J. A., Leigh, W. B. & Richmond, A. K. Younger patients
are at increased risk for graft rupture and contralateral injury after anterior
cruciate ligament reconstruction. Am. J. Sports Med. 42, 641–647 (2014).
2. Gifstad, T. et al. Long-term follow-up of patellar tendon grafts or hamstring
tendon grafts in endoscopic ACL reconstructions. Knee Surg. Sports
Traumatol. Arthrosc. 21, 576–583 (2013).
3. Alshomer, F., Chaves, C. & Kalaskar, D. M. Advances in tendon and ligament
tissue engineering: materials perspective. J. Mater. 2018, 9868151 (2018).
4. Huang, T. F. et al. Mesenchymal stem cells from a hypoxic culture improve
and engraft achilles tendon repair. Am. J. Sports Med. 41, 1117–1125 (2013).
5. Chamberlain, C. S., Saether, E. E., Aktas, E. & Vanderby, R. Mesenchymal
stem cell therapy on tendon/ligament healing. J. cytokine Biol. 2, 112 (2017).
6. Tang, Q.-M. et al. Fetal and adult fibroblasts display intrinsic differences in
tendon tissue engineering and regeneration. Sci. Rep. 4, 5515 (2014).
7. Okamoto, N. et al. Treating Achilles tendon rupture in rats with bone-marrowcell transplantation therapy. J. Bone Jt. Surg. Am. 92, 2776–2784 (2010).
8. Yang, G., Rothrauff, B. B. & Tuan, R. S. Tendon and ligament regeneration
and repair: clinical relevance and developmental paradigm. Birth Defects Res.
C. Embryo Today 99, 203–222 (2013).
9. Ni, M. et al. Tendon-derived stem cells (TDSCs) promote tendon repair in a
rat patellar tendon window defect model. J. Orthop. Res. 30, 613–619 (2012).
10. Ho, J. O., Sawadkar, P. & Mudera, V. A review on the use of cell therapy in the
treatment of tendon disease and injuries. J. Tissue Eng. 5,
2041731414549678–2041731414549678 (2014).
11. Lui, P. P. Y. Stem cell technology for tendon regeneration: current status,
challenges, and future research directions. Stem Cells Cloning 8, 163–174 (2015).
ARTICLE
12. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal
stromal cells. The International Society for Cellular Therapy position
statement. Cytotherapy 8, 315–317 (2006).
13. Nakajima, T. et al. Modeling human somite development and fibrodysplasia
ossificans progressiva with induced pluripotent stem cells. Development 145
(2018).
14. Nakajima, T., Sakurai, H. & Ikeya, M. In vitro generation of somite derivatives
from human induced pluripotent stem cells. J. Vis. Exp. https://doi.org/
10.3791/59359 (2019).
15. Nakajima, T. & Ikeya, M. Development of pluripotent stem cell-based human
tenocytes. Dev. Growth Differ. 63, 38–46 (2021).
16. Li, Y. et al. The role of scleraxis in fate determination of mesenchymal stem
cells for tenocyte differentiation. Sci. Rep. 5, 13149 (2015).
17. Chen, X. et al. Stepwise differentiation of human embryonic stem cells
promotes tendon regeneration by secreting fetal tendon matrix and
differentiation factors. Stem Cells 27, 1276–1287 (2009).
18. Lee, J. Y. et al. BMP-12 treatment of adult mesenchymal stem cells in vitro
augments tendon-like tissue formation and defect repair in vivo. PLoS ONE 6,
e17531 (2011).
19. Sassoon, A. A. et al. Skeletal muscle and bone marrow derived stromal cells: a
comparison of tenocyte differentiation capabilities. J. Orthop. Res. 30,
1710–1718 (2012).
20. Komura, S. et al. Induced pluripotent stem cell-derived tenocyte-like cells
promote the regeneration of injured tendons in mice. Sci. Rep. 10, 3992
(2020).
21. Rajpar, I. & Barrett, J. G. Optimizing growth factor induction of tenogenesis in
three-dimensional culture of mesenchymal stem cells. J. Tissue Eng. 10,
2041731419848776–2041731419848776 (2019).
22. Chen, X. et al. Force and scleraxis synergistically promote the commitment of
human ES cells derived MSCs to tenocytes. Sci. Rep. 2, 977 (2012).
23. Chen, X. et al. Scleraxis-overexpressed human embryonic stem cell-derived
mesenchymal stem cells for tendon tissue engineering with knitted silkcollagen scaffold. Tissue Eng. Part A 20, 1583–1592 (2014).
24. Brent, A. E., Schweitzer, R. & Tabin, C. J. A somitic compartment of tendon
progenitors. Cell 113, 235–248 (2003).
25. Brent, A. E. & Tabin, C. J. Developmental regulation of somite derivatives:
muscle, cartilage and tendon. Curr. Opin. Genet. Dev. 12, 548–557 (2002).
26. Benazeraf, B. & Pourquie, O. Formation and segmentation of the vertebrate
body axis. Annu. Rev. Cell Dev. Biol. 29, 1–26 (2013).
27. Ikeya, M. & Takada, S. Wnt signaling from the dorsal neural tube is required
for the formation of the medial dermomyotome. Development 125, 4969–4976
(1998).
28. Pourquié, O., Coltey, M., Teillet, M. A., Ordahl, C. & Le Douarin, N. M.
Control of dorsoventral patterning of somitic derivatives by notochord and
floor plate. Proc. Natl Acad. Sci. USA 90, 5242–5246 (1993).
29. Dubrulle, J. & Pourquie, O. Welcome to syndetome: a new somitic
compartment. Dev. Cell 4, 611–612 (2003).
30. Sakurai, H. et al. In vitro modeling of paraxial mesodermal progenitors derived
from induced pluripotent stem cells. PLoS ONE 7, e47078–e47078 (2012).
31. Chal, J. et al. Differentiation of pluripotent stem cells to muscle fiber to model
Duchenne muscular dystrophy. Nat. Biotechnol. 33, 962–969 (2015).
32. Umeda, K. et al. Human chondrogenic paraxial mesoderm, directed
specification and prospective isolation from pluripotent stem cells. Sci. Rep. 2,
455 (2012).
33. Xi, H. et al. In vivo human somitogenesis guides somite development from
hPSCs. Cell Rep. 18, 1573–1585 (2017).
34. Loh, K. M. M. et al. Mapping the pairwise choices leading from pluripotency
to human bone, heart, and other mesoderm cell types. Cell 166, 451–468
(2016).
35. Nakagawa, M. et al. A novel efficient feeder-free culture system for the
derivation of human induced pluripotent stem cells. Sci. Rep. 4, 3594 (2014).
36. Zhao, J. et al. Small molecule-directed specification of sclerotome-like
chondroprogenitors and induction of a somitic chondrogenesis program from
embryonic stem cells. Development 141, 3848–3858 (2014).
37. Pryce, B. A. et al. Recruitment and maintenance of tendon progenitors by
TGFbeta signaling are essential for tendon formation. Development 136,
1351–1361 (2009).
38. Schwarting, T. et al. Bone morphogenetic protein 7 (BMP-7) influences
tendon-bone integration in vitro. PLoS ONE 10, e0116833 (2015).
39. Schaeffer, J., Tannahill, D., Cioni, J.-M., Rowlands, D. & Keynes, R.
Identification of the extracellular matrix protein Fibulin-2 as a regulator of
spinal nerve organization. Dev. Biol. 442, 101–114 (2018).
40. Murrell, G. A. et al. The achilles functional index. J. Orthop. Res. 10, 398–404
(1992).
41. Molloy, T., Wang, Y. & Murrell, G. The roles of growth factors in tendon and
ligament healing. Sports Med. 33, 381–394 (2003).
42. Hwa, V., Oh, Y. & Rosenfeld, R. G. The insulin-like growth factor-binding
protein (IGFBP) superfamily. Endocr. Rev. 20, 761–787 (1999).
NATURE COMMUNICATIONS | (2021)12:5012 | https://doi.org/10.1038/s41467-021-25328-6 | www.nature.com/naturecommunications
11
A Self-archived copy in
Kyoto University Research Information Repository
https://repository.kulib.kyoto-u.ac.jp
ARTICLE
NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25328-6
43. Robertson, I. B. et al. Latent TGF-beta-binding proteins. Matrix Biol. 47,
44–53 (2015).
44. Kurtz, C. A., Loebig, T. G., Anderson, D. D., DeMeo, P. J. & Campbell, P. G.
Insulin-like growth factor I accelerates functional recovery from achilles
tendon injury in a rat model. Am. J. Sports Med. 27, 363–369 (1999).
45. Bortz, W. M. 2nd The disuse syndrome. West. J. Med. 141, 691–694 (1984).
46. Lee, J., Smeriglio, P., Chu, C. R. & Bhutani, N. Human iPSC-derived chondrocytes
mimic juvenile chondrocyte function for the dual advantage of increased
proliferation and resistance to IL-1beta. Stem Cell Res. Ther. 8, 244 (2017).
47. Mandai, M. et al. iPSC-derived retina transplants improve vision in rd1 endstage retinal-degeneration mice. Stem cell Rep. 8, 69–83 (2017).
48. Schweitzer, R. et al. Analysis of the tendon cell fate using Scleraxis, a specific
marker for tendons and ligaments. Development 128, 3855–3866 (2001).
49. Fertin, C. et al. Interleukin-4 stimulates collagen synthesis by normal and
scleroderma fibroblasts in dermal equivalents. Cell. Mol. Biol. 37, 823–829 (1991).
50. Sempowski, G. D., Derdak, S. & Phipps, R. P. Interleukin-4 and interferongamma discordantly regulate collagen biosynthesis by functionally distinct
lung fibroblast subsets. J. Cell. Physiol. 167, 290–296 (1996).
51. Mahboubi, S., Glaser, D. L., Shore, E. M. & Kaplan, F. S. Fibrodysplasia
ossificans progressiva. Pediatr. Radiol. 31, 307–314 (2001).
52. Smith, Z. A., Buchanan, C. C., Raphael, D. & Khoo, L. T. Ossification of the
posterior longitudinal ligament: pathogenesis, management, and current
surgical approaches. A review. Neurosurg. Focus 30, E10 (2011).
53. Chan, K.-M. & Fu, S.-C. Anti-inflammatory management for tendon injuries friends or foes? Sports Med. Arthrosc. Rehabil. Ther. Technol. 1, 23 (2009).
54. Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma
by single-cell RNA-seq. Science 352, 189–196 (2016).
55. Wang, T. et al. Functional evaluation outcomes correlate with
histomorphometric changes in the rat sciatic nerve crush injury model: a
comparison between sciatic functional index and kinematic analysis. PLoS
ONE 13, e0208985 (2018).
56. Yamana, R. et al. Rapid and deep profiling of human induced pluripotent stem
cell proteome by one-shot NanoLC-MS/MS analysis with meter-scale
monolithic silica columns. J. Proteome Res. 12, 214–221 (2013).
57. Rappsilber, J., Ishihama, Y. & Mann, M. Stop And Go Extraction tips for
matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS
sample pretreatment in proteomics. Anal. Chem. 75, 663–670 (2003).
58. Hahne, H. et al. DMSO enhances electrospray response, boosting sensitivity of
proteomic experiments. Nat. Methods 10, 989–991 (2013).
59. Nesvizhskii, A. I. & Aebersold, R. Interpretation of shotgun proteomic data.
Mol. Cell. Proteom. 4, 1419–1440 (2005).
60. Iwasaki, M., Tabata, T., Kawahara, Y., Ishihama, Y. & Nakagawa, M. Removal
of interference MS/MS spectra for accurate quantification in isobaric tagbased proteomics. J. Proteome Res. 18, 2535–2544 (2019).
61. Moriya, Y. et al. The jPOST environment: an integrated proteomics data
repository and database. Nucleic Acids Res. 47, D1218–D1224 (2018).
Acknowledgements
We thank Drs. D. Murata, D. Kamiya, Y. Toyooka, and N. Boyd-Gibbins for invaluable
discussions, comments, and critical reading of the manuscript, M. Terashima, and Y.
Inada for technical support, Dr. M. Nomura, K. Ohnishi, and J. Kuwahara for single-cell
12
RNA sequencing, and all members of the Ikeya laboratory for their support in this study.
This work was supported by the Japan Society for the Promotion of Science (JSPS)
KAKENHI grant number 20H03803 (to M.Ik.), the Core Center for iPS Cell Research of
the Research Center Network for Realization of Regenerative Medicine
(20bm0104001h0008) and the Projects for Technical Development, which is a program
of the Research Center Network for Realization of Regenerative Medicine
(20bm0404066h0001), from the Japan Agency for Medical Research and Development
(AMED) (to M.Ik.), a grant from the iPS Cell Research Fund (to M.Ik.), and a research
grant from the Fujiwara Memorial Foundation (to T.N.).
Author contributions
T.N.: Conception and design, data collection and assembly, data analysis and interpretation, manuscript writing, final approval of the manuscript; A.N., N.Y., K.Y., C.Z.:
Data collection and assembly; T.K.: Analysis and interpretation of single-cell RNA
sequencing data; M.Iw.: experimental design and proteome data interpretation; H.K.:
administrative support; M.Ik.: Conception and design, financial support, administrative
support, data interpretation, manuscript writing, final approval of the manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41467-021-25328-6.
Correspondence and requests for materials should be addressed to T.N. or M.I.
Peer review information Nature Communications thanks the anonymous reviewer(s) for
their contribution to the peer review of this work. Peer reviewer reports are available.
Reprints and permission information is available at http://www.nature.com/reprints
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
© The Author(s) 2021
NATURE COMMUNICATIONS | (2021)12:5012 | https://doi.org/10.1038/s41467-021-25328-6 | www.nature.com/naturecommunications
...
論文の公開元へ
