title: Stromal cell-derived factor-1 and monocyte chemotactic protein-3 improve recruitment of osteogenic cells into sites of musculoskeletal repair.
abstract: Homing of osteogenic cells through the systemic circulation represents an alternative to traditional orthopedic tissue engineering approaches that focus on local cell populations. We hypothesize that expression of the chemokine, stromal cell-derived factor-1 (SDF-1) or monocyte chemotactic protein-3 (MCP-3) may enhance homing of osteogenic cells into sites of fracture repair, as both have demonstrated promise in recruitment of marrow stromal cells (MSCs). This hypothesis was tested by transplantation of culture expanded MSCs expressing these factors adjacent to a fracture site on a collagen scaffold. One green fluorescent protein positive (GFP+) and one wild-type mouse were surgically conjoined as parabiots at 7-8 weeks of age. Fibular osteotomy was performed 4 weeks after parabiosis on the hind limb of the wild-type mouse. Mice were randomly allocated to receive one of the following five treatments: control (no scaffold), empty scaffold (no cells), or scaffold containing MSCs, scaffold containing MSCs expressing SDF-1, or scaffold containing MSCs expressing MCP-3. Fracture callus was harvested 2 weeks after injury, and analyzed with confocal microscopy and cell-counting software. When compared to fracture callus treated with nontransfected MSCs, the fracture callus of mice treated with both SDF-1 and MCP-3 secreting MSCs demonstrated a significant increase in the number of both GFP+ cells (p = 0.0003, p = 0.02) and GFP+ /AP+ cells (p = 0.0005, p = 0.01). These data suggest that homing of osteogenic cells from systemic circulation participate in fracture repair and that homing pathways might be modulated to enhance the contribution of circulating progenitors at the site of skeletal injury.
authors.affiliation: Orthopaedic Research Center, Cleveland Clinic, Department of Biomedical Engineering, Cleveland, Ohio 44195, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shinohara
authors.forename: Stephen
authors.initials: S
authors.lastname: Greenfield
authors.forename: Hui
authors.initials: H
authors.lastname: Pan
authors.forename: Amit
authors.initials: A
authors.lastname: Vasanji
authors.forename: Ken
authors.initials: K
authors.lastname: Kumagai
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Midura
authors.forename: Matthew
authors.initials: M
authors.lastname: Kiedrowski
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
authors.forename: George F
authors.initials: GF
authors.lastname: Muschler
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D054410:Chemokine CCL7 / Q000235:genetics* / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017102:Fracture Healing / Q000502:physiology*; D050723:Fractures, Bone / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010011:Osteocytes / Q000166:cytology / Q000502:physiology*
chemical_list: C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D049452:Green Fluorescent Proteins