title: Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects.
abstract: Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC(IGF)), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC(IGF) or traceable MSC(IGF)-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1(-/-)) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSC(IGF) through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC(IGF) to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1(-/-) mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1(-/-) left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC(IGF) in fracture repair and potentially to treat nonunions.
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Froilán
authors.initials: F
authors.lastname: Granero-Moltó
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Myers
authors.forename: Jared A
authors.initials: JA
authors.lastname: Weis
authors.forename: Lara
authors.initials: L
authors.lastname: Longobardi
authors.forename: Tieshi
authors.initials: T
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Yan
authors.forename: Natasha
authors.initials: N
authors.lastname: Case
authors.forename: Janet
authors.initials: J
authors.lastname: Rubin
authors.forename: Anna
authors.initials: A
authors.lastname: Spagnoli
mesh_terms: D000818:Animals; D002146:Bony Callus / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D054443:Cell Migration Assays; D005260:Female; D017102:Fracture Healing; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010012:Osteogenesis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I