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Circulating Osteogenic Cells in Periarticular Non-hereditary Heterotopic Ossification

Circulating Osteogenic Cells in Periarticular Non-hereditary Heterotopic Ossification. Robert J. Pignolo, M.D., Ph.D. University of Pennsylvania. Age. Young. Old. Normal Bone Formation & Remodeling. Osteoporosis. Skeleton. Location. Heterotopic Ossification. Heterotopic

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Circulating Osteogenic Cells in Periarticular Non-hereditary Heterotopic Ossification

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  1. Circulating Osteogenic Cells in Periarticular Non-hereditary Heterotopic Ossification Robert J. Pignolo, M.D., Ph.D. University of Pennsylvania

  2. Age Young Old Normal Bone Formation & Remodeling Osteoporosis Skeleton Location Heterotopic Ossification Heterotopic Ossification Soft Tissue Dysfunctional bone formation: Errors in time and place

  3. Clinical Settings for Non-Hereditary Forms of Heterotopic Ossification Pignolo & Foley CRBMM 3: 261-6 (2005)

  4. Conditions that Predispose to Non-Heredity Heterotopic Ossification • Post-arthroplasty • Traumatic brain injury • Spinal cord injury • CVA • Non-neurologic trauma Pignolo & Foley CRBMM 3: 261-6 (2005)

  5. Periarticular involvement of non-hereditary HO after traumatic brain injury Garland, DE et al JBJS Am62: 1143-46 (1980)

  6. Circulating Osteogenic Precursor (COP) Cells • Circulating mononuclear cells • Plastic/glass adherence • Markers of osteoblast-like cells • Hematopoietic origin • Ability to form a mineralized matrix in vitro or bone in vivo. • Found in early lesions of heterotopic ossification in FOP Suda et al Stem Cells 27: 2209-19 (2009)

  7. COP cells are present in pre-osseous fibroproliferative lesions of FOP CD45 Type I Col CD45 + Type I Col CD45 + Type I Col + DAPI Suda et al Stem Cells 27: 2209-19 (2009)

  8. Col I CD 45 Merge Merge +DAPI Standard Confocal Pre-immune COP cells are present in pre-osseous fibroproliferative lesions of FOP Suda et al Stem Cells 27: 2209-19 (2009)

  9. Merge + DAPI Pre- immune CD45 Col 1 Trauma CVA THA TBI SCI COP cells are present in lesions of NHHO

  10. CD45 COL 1 DAPI + Merge Lymph Node Brain COP cells are absent in unaffected tissue

  11. Perivascular Lymphocytic Infiltration Fibroproliferation Infiltration into Soft tissue Early stages Mature bone Cartilage formation Neovascularity Late stages Stages of NHHO lesion formation

  12. COP cells are found in early stage lesions 400X Merge with DAPI Collagen CD 45

  13. 200X 400X CD45 OCN DAPI + Merge CD45+ OCN+ COP Cells

  14. CD45/OCN near blood vessel - trauma COP cells near blood vessel CD45…Red OCN….Green DAPI.…Blue

  15. COP Cells in Peri-articular Non-hereditary HO Lesions

  16. Heterotopic Bone Soft Tissue (non-skeletal) INJURY Bone Marrow Endochondral bone formation CXCR4 INFLAMATION Release of inflammatory cytokines, migratory factors (e.g., SDF-1) COP cells CXCR4 Otsuru S et al BBRC 354: 453-8 (2007) Otsuru S et al Stem Cells 26: 223-34 (2008) Suda RK et al Stem Cells 27: 2209-19 (2009) COP cell involvement in HO Pignolo & Foley CRBMM 3: 261-6 (2005) Kan L et al Stem Cells 27: 150-6 (2009)

  17. Summary • COP cells are present in lesions of periarticular non-hereditary heterotopic ossification (NHHO) • COP cells are associated with early fibroproliferative and neovascular stages of lesion formation in HO, but absent in regions of unaffected tissue (no HO) • Osteogenic cells in the blood home to distant sites where they are associated with formation of HO caused by diverse traumatic conditions.

  18. Acknowledgements Funding: Laboratory: Kevin Egan Elizabeth Russell Lakshman Singh Robin Suda Jung-Hoon Kim Haitao Wang Jill Brodsky Collaborators: Brad Johnson, Univ of Penn Yongwon Choi, Univ of Penn Eric Brown, Univ of Penn Alex Wright, Univ of Penn Steve Emerson, Haverford Univ Peter Adams, Beatson Institute Mary Ann Keenan, Univ of Penn John Esterhai, Univ of Penn Samir Mehta, Univ of Penn

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