Activin A marks a novel progenitor cell population during fracture healing and reveals a therapeutic strategy

  1. Lutian Yao
  2. Jiawei Lu
  3. Leilei Zhong
  4. Yulong Wei
  5. Tao Gui
  6. Luqiang Wang
  7. Jaimo Ahn
  8. Joel D Boerckel
  9. Danielle Rux
  10. Christina Mundy
  11. Ling Qin  Is a corresponding author
  12. Maurizio Pacifici  Is a corresponding author
  1. Children's Hospital of Philadelphia, United States
  2. University of Pennsylvania, United States
  3. University of Michigan-Ann Arbor, United States

Abstract

Insufficient bone fracture repair represents a major clinical and societal burden and novel strategies are needed to address it. Our data reveal that the TGF-β superfamily member Activin A became very abundant during mouse and human bone fracture healing but was minimally detectable in intact bones. Single cell RNA-sequencing revealed that the Activin A-encoding gene Inhba was highly expressed in a unique, highly proliferative progenitor cell (PPC) population with a myofibroblast character that quickly emerged after fracture and represented the center of a developmental trajectory bifurcation producing cartilage and bone cells within callus. Systemic administration of neutralizing Activin A antibody inhibited bone healing. In contrast, a single recombinant Activin A implantation at fracture site in young and aged mice boosted: PPC numbers; phosphorylated SMAD2 signaling levels; and bone repair and mechanical properties in endochondral and intramembranous healing models. Activin A directly stimulated myofibroblastic differentiation, chondrogenesis and osteogenesis in periosteal mesenchymal progenitor culture. Our data identify a distinct population of Activin A-expressing PPCs central to fracture healing and establish Activin A as a potential new therapeutic tool.

Data availability

All data needed to evaluate the conclusions of this study are present in the paper and/or Supplemental Material. Sequencing data have been deposited in GEO under accession code GSE192630

The following data sets were generated

Article and author information

Author details

  1. Lutian Yao

    Translational Research Program in Pediatric Orthopaedics, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0652-2075
  2. Jiawei Lu

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Leilei Zhong

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1153-4115
  4. Yulong Wei

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3823-9984
  5. Tao Gui

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Luqiang Wang

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jaimo Ahn

    Department of Orthopaedic Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Joel D Boerckel

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3126-3025
  9. Danielle Rux

    Translational Research Program in Pediatric Orthopaedics, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Christina Mundy

    Translational Research Program in Pediatric Orthopaedics, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3328-5965
  11. Ling Qin

    Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States
    For correspondence
    qinling@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2582-0078
  12. Maurizio Pacifici

    Translational Research Program in Pediatric Orthopaedics, Children's Hospital of Philadelphia, Philadelphia, United States
    For correspondence
    pacificim@email.chop.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6854-4942

Funding

National Institutes of Health (R01AR071946)

  • Maurizio Pacifici

National Institutes of Health (R21AR074570)

  • Ling Qin

National Institutes of Health (R01AG069401)

  • Ling Qin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The experimental animal protocols were approved by the Institutional Animal Care and Use Committees of the University of Pennsylvania (IACUC#804112) and the Children's Hospital of Philadelphia (IACUC#20-000958). The experiments were performed in the animal facilities of both institutions, which implement strict regimens for animal care and use.

Copyright

© 2023, Yao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lutian Yao
  2. Jiawei Lu
  3. Leilei Zhong
  4. Yulong Wei
  5. Tao Gui
  6. Luqiang Wang
  7. Jaimo Ahn
  8. Joel D Boerckel
  9. Danielle Rux
  10. Christina Mundy
  11. Ling Qin
  12. Maurizio Pacifici
(2023)
Activin A marks a novel progenitor cell population during fracture healing and reveals a therapeutic strategy
eLife 12:e89822.
https://doi.org/10.7554/eLife.89822

Share this article

https://doi.org/10.7554/eLife.89822

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