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Defining The Role Of The Vasculogenic Niche In Trauma-induced Heterotopic Ossification Using Novel Imaging and Lineage-tracing Mice
Shailesh Agarwal, MD1, Shawn J. Loder, BS1, Cameron Brownley, BS1, Jonathan Peterson, BS1, Eboda Oluwatobi, BS1, Ronald Tompkins, MD2, David Herndon, MD3, Dolrudee Jumlongras, DDS, PhD4, Bjorn Olsen, MD, PhD4, Steven R. Buchman, MD1, Paul S. Cederna, MD1, Benjamin Levi, MD1.
1University of Michigan, Ann Arbor, MI, USA, 2Massachusetts General Hospital, Boston, MA, USA, 3University of Texas Medical Branch, Galveston, TX, USA, 4Harvard School of Dental Medicine, Boston, MA, USA.

PURPOSE: Heterotopic ossification (HO) is the formation of bone in soft tissues following trauma. We hypothesized that early vascularity establishes the niche for HO, and that endothelial cells contribute to HO.
METHODS: Tissue from 244 patients with >20% TBSA burn within 96 hours was compared to 34 non-burn controls for vasculogenic gene expression. Separately, C57BL/6 mice underwent Achilles’ tenotomy with 30% TBSA burn or no burn. The vasculogenic niche of the tenotomy site was assessed using flow cytometry, lineage-tracing mice, bioluminescent and microCT imaging, and mRNA quantification using microcapture.
RESULTS: Tissue from burn patients demonstrated significant up-regulation of vasculogenic genes (VEGF/HIF-1alpha/VE-cadherin/CD31) compared to controls. Flow cytometry of cells from our mouse model showed 20% enrichment of mature endothelial cells (Tie2+/CD31+) and 100% enrichment of endothelial progenitor cells (CD34+/CD133+) at the tenotomy site compared with uninjured leg(A;p <0.05). At two weeks, bioluminescent imaging demonstrated increased vascularity at the future HO site compared to contralateral control limbs(B/C). Three weeks after trauma, Cdh5+/0-Cre/RFP+/+ lineage-tracing mice demonstrated enrichment of endothelial progenitor cells at the tenotomy site compared with the contralateral control limb(D). At 6 weeks after injury, HO lacked cells of endothelial origin.
CONCLUSIONS: An early, vasculogenic niche enhances HO. Mice with robust HO demonstrate enrichment of mature endothelial cells and endothelial precursor cells. Although endothelial progenitor cells contribute to vasculogenesis, they likely do not contribute to HO osteoblasts.


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