title: Upregulating CXCR4 in human fetal mesenchymal stem cells enhances engraftment and bone mechanics in a mouse model of osteogenesis imperfecta.
abstract: Stem cells have considerable potential to repair damaged organs and tissues. We previously showed that prenatal transplantation of human first trimester fetal blood mesenchymal stem cells (hfMSCs) in a mouse model of osteogenesis imperfecta (oim mice) led to a phenotypic improvement, with a marked decrease in fracture rate. Donor cells differentiated into mature osteoblasts, producing bone proteins and minerals, including collagen type Iα2, which is absent in nontransplanted mice. This led to modifications of the bone matrix and subsequent decrease of bone brittleness, indicating that grafted cells directly contribute to improvement of bone mechanical properties. Nevertheless, the therapeutic effect was incomplete, attributing to the limited level of engraftment in bone. In this study, we show that although migration of hfMSCs to bone and bone marrow is CXCR4-SDF1 (SDF1 is stromal-derived factor) dependent, only a small number of cells present CXCR4 on the cell surface despite high levels of internal CXCR4. Priming with SDF1, however, upregulates CXCR4 to increase the CXCR4(+) cell fraction, improving chemotaxis in vitro and enhancing engraftment in vivo at least threefold in both oim and wild-type bone and bone marrow. Higher engraftment in oim bones was associated with decreased bone brittleness. This strategy represents a step to improve the therapeutic benefits of fetal cell therapy toward being curative.
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Gemma N
authors.initials: GN
authors.lastname: Jones
authors.forename: Dafni
authors.initials: D
authors.lastname: Moschidou
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lay
authors.forename: Hassan
authors.initials: H
authors.lastname: Abdulrazzak
authors.forename: Maximilien
authors.initials: M
authors.lastname: Vanleene
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shefelbine
authors.forename: Julia
authors.initials: J
authors.lastname: Polak
authors.forename: Paolo
authors.initials: P
authors.lastname: de Coppi
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Fisk
authors.forename: Pascale V
authors.initials: PV
authors.lastname: Guillot
mesh_terms: D000818:Animals; D001857:Bone Matrix / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis; D024042:Collagen Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D050723:Fractures, Bone / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D024042:Collagen Type I; D019718:Receptors, CXCR4