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Original Article | Open Access

Tppp3+ synovial/tendon sheath progenitor cells contribute to heterotopic bone after trauma

Ji-Hye Yea1,, Mario Gomez-Salazar1,, Sharon Onggo1, Zhao Li1, Neelima Thottappillil1, Masnsen Cherief1, Stefano Negri1,2, Xin Xing1, Qizhi Qin1, Robert Joel Tower3, Chen-Ming Fan4, Benjamin Levi3, Aaron W. James1 ( )
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Orthopaedic and Trauma Surgery Unit, Department of Surgery, Dentistry, Paediatrics and Gynaecology of the University of Verona, Verona, Italy
Center for Organogenesis and Trauma, Department of Surgery, University of Texas Southwestern, Dallas, TX, USA
Carnegie Institution for Science, Baltimore, MD, USA

These authors contributed equally: Ji-Hye Yea, Mario Gomez-Salazar

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Abstract

Heterotopic ossification (HO) is a pathological process resulting in aberrant bone formation and often involves synovial lined tissues. During this process, mesenchymal progenitor cells undergo endochondral ossification. Nonetheless, the specific cell phenotypes and mechanisms driving this process are not well understood, in part due to the high degree of heterogeneity of the progenitor cells involved. Here, using a combination of lineage tracing and single-cell RNA sequencing (scRNA-seq), we investigated the extent to which synovial/tendon sheath progenitor cells contribute to heterotopic bone formation. For this purpose, Tppp3 (tubulin polymerization-promoting protein family member 3)-inducible reporter mice were used in combination with either Scx (Scleraxis) or Pdgfra (platelet derived growth factor receptor alpha) reporter mice. Both tendon injury- and arthroplasty-induced mouse experimental HO models were utilized. ScRNA-seq of tendon-associated traumatic HO suggested that Tppp3 is an early progenitor cell marker for either tendon or osteochondral cells. Upon HO induction, Tppp3 reporter+ cells expanded in number and partially contributed to cartilage and bone formation in either tendon- or joint-associated HO. In double reporter animals, both Pdgfra+Tppp3+ and Pdgfra+Tppp3- progenitor cells gave rise to HO-associated cartilage. Finally, analysis of human samples showed a substantial population of TPPP3-expressing cells overlapping with osteogenic markers in areas of heterotopic bone. Overall, these data demonstrate that synovial/tendon sheath progenitor cells undergo aberrant osteochondral differentiation and contribute to HO after trauma.

References

1

Negri, S. et al. Acetabular reaming is a reliable model to produce and characterize periarticular heterotopic ossification of the hip. Stem Cell Transl. Med. 11, 876–888 (2022).
Crossref Google Scholar
2

McCarthy, E. & Sundaram, M. Heterotopic ossification: a review. Skeletal Radiol. 34, 609–619 (2005).
Crossref Google Scholar
3

Lin, L., Shen, Q., Xue, T. & Yu, C. Heterotopic ossification induced by Achilles tenotomy via endochondral bone formation: expression of bone and cartilage related genes. Bone 46, 425–431 (2010).
Crossref Google Scholar
4

Meyers, C. et al. Heterotopic Ossification: A Comprehensive Review. JBMR Plus. 3, e10172 (2019).
Crossref Google Scholar
5

Wittenberg, R. H., Peschke, U. & Botel, U. Heterotopic ossification after spinal-cord injury-epidemiology and risk-factors. J. Bone Joint Surgery-British Volume 74, 215–218 (1992).
Crossref Google Scholar
6

Garland, D. E. Clinical observations on fractures and heterotopic ossification in the spinal-cord and traumatic brain injured populations. Clin. Orthop. Relat. R 233, 86–101 (1988).
Crossref Google Scholar
7

Kan, C. et al. Microenvironmental factors that regulate mesenchymal stem cells: lessons learned from the study of heterotopic ossification. Histol. Histopathol. 32, 977–985 (2017).
Google Scholar
8

Nelson, E. R., Wong, V. W., Krebsbach, P. H., Wang, S. C. & Levi, B. Heterotopic ossification following burn injury: the role of stem cells. J. Burn Care Res. 33, 463–470 (2012).
Crossref Google Scholar
9

Zhang, Q., Zhou, D., Wang, H. T. & Tan, J. Heterotopic ossification of tendon and ligament. J. Cellular Mol. Med. 24, 5428–5437 (2020).
Crossref Google Scholar
10

Agarwal, S. et al. Scleraxis-lineage cells contribute to ectopic bone formation in muscle and tendon. Stem Cells 35, 705–710 (2017).
Crossref Google Scholar
11

Pagani, C. A. et al. Novel lineage-tracing system to identify site-specific ectopic bone precursor cells. Stem Cell Rep.16, 626–640 (2021).
Crossref Google Scholar
12

Regard, J. B. et al. Activation of hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat. Med. 19, 1505–1512 (2013).
Crossref Google Scholar
13

Dey, D. et al. Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci. Transl. Medicine 8, 366ra163 (2016).
Crossref Google Scholar
14

Kan, C. et al. Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. Bone 109, 71–79 (2018).
Crossref Google Scholar
15

Farahani, R. M. & Xaymardan, M. Platelet-derived growth factor receptor alpha as a marker of mesenchymal stem cells in development and stem cell biology. Stem Cells Int. 2015, 362753 (2015).
Crossref Google Scholar
16

Bi, Y. et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat. Med. 13, 1219–1227 (2007).
Crossref Google Scholar
17

Lee, C. H. et al. Harnessing endogenous stem/progenitor cells for tendon regeneration. J. Clinical Invest. 125, 2690–2701 (2015).
Crossref Google Scholar
18

Gumucio, J. P., Schonk, M. M., Kharaz, Y. A., Comerford, E. & Mendias, C. L. Scleraxis is required for the growth of adult tendons in response to mechanical loading. JCI Insight 5, e138295 (2020).
Crossref Google Scholar
19

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, 1490–1503 (2019).
Crossref Google Scholar
20

Lee, S. Y. et al. NGF-TrkA signaling dictates neural in growth and aberrant osteochondral differentiation after soft tissue trauma. Nat. Commun. 12, 4939 (2021).
Crossref Google Scholar
21

Staverosky, J. A., Pryce, B. A., Watson, S. S. & Schweitzer, R. Tubulin polymerization‐promoting protein family member 3, Tppp3, is a specific marker of the differentiating tendon sheath and synovial joints. Dev. Dyn. 238, 685–692 (2009).
Crossref Google Scholar
22

Zhang, Y.-J. et al. Concise review: stem cell fate guided by bioactive molecules for tendon regeneration. Stem Cell Transl. Med. 7, 404–414 (2018).
Crossref Google Scholar
23

Convente, M. R., Wang, H. T., Pignolo, R. J., Kaplan, F. S. & Shore, E. M. The immunological contribution to heterotopic ossification disorders. Curr. Osteoporos. Rep. 13, 116–124 (2015).
Crossref Google Scholar
24

Hwang, C. et al. Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification. Bone Res. 7, 36 (2019).
Crossref Google Scholar
25

Yang, L., Tsang, K. Y., Tang, H. C., Chan, D. & Cheah, K. S. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc. Natl. Acad. Sci. 111, 12097–12102 (2014).
Crossref Google Scholar
26

Tarafder, S. et al. Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling. Faseb J. 31, 3991–3998 (2017).
Crossref Google Scholar
27

Hsu, G. C. Y. et al. Endogenous CCN family member WISP1 inhibits traumainduced heterotopic ossification. JCI Insight 5, e135432 (2020).
Crossref Google Scholar
28

Yea, J.-H., Bae, T. S., Kim, B. J., Cho, Y. W. & Jo, C. H. Regeneration of the Rotator Cuff Tendon-to-Bone Interface using Umbilical Cord-Derived Mesenchymal Stem Cells and Gradient Extracellular Matrix Scaffolds from Adipose Tissue in a Rat Model. Acta Biomater. 114, 104–116 (2020).
Crossref Google Scholar
29

Yea, J.-H. et al. Regeneration of a full-thickness defect of rotator cuff tendon with freshly thawed umbilical cord-derived mesenchymal stem cells in a rat model. Stem Cell Res. Ther. 11, 1–13 (2020).
Crossref Google Scholar
30

Yea, J. H. et al. Regeneration of a full-thickness defect in rotator cuff tendon with umbilical cord-derived mesenchymal stem cells in a rat model. PLoS One 15, e0235239 (2020).
Crossref Google Scholar
31

Qin, Q. Z. et al. Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma. Bone Res. 10, 43 (2022).
Crossref Google Scholar
32

Qiu, X. J. et al. Reversed graph embedding resolves complex single-cell trajectories. Nat. Methods 14, 979–982 (2017).
Crossref Google Scholar
33

Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).
Crossref Google Scholar
Bone Research
Volume 11,
December 2023
Article number: 39
DOI: 10.1038/s41413-023-00272-x
Cite this article:
Yea J-H, Gomez-Salazar M, Onggo S, et al. Tppp3+ synovial/tendon sheath progenitor cells contribute to heterotopic bone after trauma. Bone Research, 2023, 11: 39. https://doi.org/10.1038/s41413-023-00272-x

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Received: 30 December 2022
Revised: 18 May 2023
Accepted: 28 May 2023
Published: 21 July 2023
© The Author(s) 2023

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