title: Analysis of Bone-Cartilage-Stromal Progenitor Populations in Trauma Induced and Genetic Models of Heterotopic Ossification.
abstract: Heterotopic ossification (HO), the formation of extra-skeletal bone in soft tissues, is a pathologic process occurring after substantial burns or trauma, or in patients with type I bone morphogenetic protein (BMP) receptor hyperactivating mutations. Identifying the cells responsible for de novo bone formation during adulthood is of critical importance for therapeutic and regenerative purposes. Using a model of trauma-induced HO with hind limb Achilles' tenotomy and dorsal burn injury and a genetic nontrauma HO model (Nfatc1-Cre/caAcvr1(fl/wt) ), we demonstrate enrichment of previously defined bone-cartilage-stromal progenitor cells (BCSP: AlphaV+/CD105+/Tie2-/CD45-/Thy1-/6C3-) at the site of HO formation when compared with marrow isolated from the ipsilateral hind limb, or from tissue of the contralateral, uninjured hind limb. Upon transplantation into tenotomy sites soon after injury, BCSPs isolated from neonatal mice or developing HO incorporate into the developing lesion in cartilage and bone and express chondrogenic and osteogenic transcription factors. Additionally, BCSPs isolated from developing HO similarly incorporate into new HO lesions upon transplantation. Finally, adventitial cells, but not pericytes, appear to play a supportive role in HO formation. Our findings indicate that BCSPs contribute to de novo bone formation during adulthood and may hold substantial regenerative potential. Stem Cells 2016;34:1692-1701.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Loder
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sorkin
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Shuli
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology & Laboratory Medicine and Orthopaedic Hospital Research Center, University of California, Los Angeles.
authors.forename: Swati
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Pathology & Laboratory Medicine and Orthopaedic Hospital Research Center, University of California, Los Angeles.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: James
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levi
mesh_terms: D000125:Achilles Tendon / Q000473:pathology / Q000601:surgery; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000166:cytology*; D002356:Cartilage / Q000166:cytology*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D009999:Ossification, Heterotopic / Q000209:etiology* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D010006:Osteoblasts / Q000473:pathology; D010012:Osteogenesis; D020286:Pericytes / Q000473:pathology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D017154:Stromal Cells / Q000166:cytology; D058971:Tenotomy; D014947:Wounds and Injuries / Q000150:complications* / Q000473:pathology
keywords: Bone; Bone marrow stromal cells; Cell migration; Chondrogenesis; Experimental models; Pericytes; Progenitor cells