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Direct Mouse Trauma/Burn Model of Heterotopic Ossification
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Progenitors in Peripheral Nerves Launch Heterotopic Ossification.

Elizabeth A Olmsted-Davis1,2, Elizabeth A Salisbury1, Diana Hoang1

  • 1Center for Cell and Gene Therapy.

Stem Cells Translational Medicine
|February 16, 2017
PubMed
Summary

Bone morphogenetic protein type 2 (BMP2) triggers heterotopic ossification (HO) via nerve-derived progenitors. These neural progenitors in the endoneurium initiate bone formation in both mouse models and human patients with HO.

Keywords:
Blood-nerve barrierBone morphogenetic type 2Heterotopic ossificationNeural stem cellsTrauma

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Area of Science:

  • Regenerative Medicine
  • Stem Cell Biology
  • Skeletal Biology

Background:

  • Heterotopic ossification (HO) is abnormal bone formation outside the skeleton.
  • The cellular origins of HO remain incompletely understood.
  • Bone morphogenetic protein type 2 (BMP2) is a potent inducer of HO.

Purpose of the Study:

  • To identify the progenitor cells responsible for BMP2-induced HO.
  • To investigate the neural origin of HO progenitors.
  • To confirm the presence of these progenitors in human HO tissues.

Main Methods:

  • Murine model of BMP2-induced HO.
  • Tamoxifen-inducible Wnt1-Cre;Ai9 reporter mice for lineage tracing.
  • Immunohistochemistry for phosphoSMAD (PS), osterix (SP7), Sox9, and UCP1.
  • Fluorescence-activated cell sorting (FACS).
  • Analysis of human HO patient tissues.

Main Results:

  • BMP2 signaling activates progenitors within the endoneurium of peripheral nerves.
  • Lineage tracing confirmed neural origin of HO progenitors (SP7+TR+ cells).
  • These progenitors are multipotent, differentiating into pre-chondrocytes and brown fat precursors.
  • Human HO tissues show increased PS+ cells in nerves and SP7+ cells in nerves and on bone.

Conclusions:

  • The endoneurium of peripheral nerves contains multipotent progenitors that initiate HO.
  • These neural-derived progenitors are conserved between mouse models and human HO.
  • Targeting these endoneurial progenitors may offer therapeutic strategies for HO.