Activin A marks a novel progenitor cell population during fracture healing and reveals a therapeutic strategy
- Children's Hospital of Philadelphia, United States
- University of Pennsylvania, United States
- 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
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Activin A promotes mouse bone fracture repair and characterizes a novel myofibroblastic population in callusNCBI Gene Expression Omnibus, GSE192630.
Article and author information
Author details
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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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
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