Progenitors in peripheral nerves launch heterotopic ossification

Elizabeth A. Olmsted-Davis, Elizabeth A. Salisbury, Diana Hoang, Eleanor L. Davis, Zawaunyka Lazard, Corinne Sonnet, Thomas A. Davis, Jonathan A. Forsberg, Alan R. Davis

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)-induced heterotopic ossification (HO) show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen-regulated Wnt1-Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP71(osterix1)TR1 cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR1 and TR2 cells isolated by fluorescence-activated cell sorting showed that all SP71 cells were found in the TR1 population, whereas only about 80% of the TR1 cells expressed SP7. Pre-chondrocytes (Sox 91) and transient brown fat (tBAT, UCP11) also coexpressed TR, suggesting that the progenitor in nerves is multi-potential. The endoneurium of human nerves near the site of HO contained many PS1 cells, and SP71 cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS1 and SP71 cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO.

Original languageEnglish (US)
Pages (from-to)1109-1119
Number of pages11
JournalStem Cells Translational Medicine
Volume6
Issue number4
DOIs
StatePublished - Apr 2017

Keywords

  • Blood-nerve barrier
  • Bone morphogenetic type 2
  • Heterotopic ossification
  • Neural stem cells
  • Trauma

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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  • Cite this

    Olmsted-Davis, E. A., Salisbury, E. A., Hoang, D., Davis, E. L., Lazard, Z., Sonnet, C., Davis, T. A., Forsberg, J. A., & Davis, A. R. (2017). Progenitors in peripheral nerves launch heterotopic ossification. Stem Cells Translational Medicine, 6(4), 1109-1119. https://doi.org/10.1002/sctm.16-0347