title: Improved Mobilization of Exogenous Mesenchymal Stem Cells to Bone for Fracture Healing and Sex Difference.
abstract: Mesenchymal stem cell (MSC) transplantation has been tested in animal and clinical fracture studies. We have developed a bone-seeking compound, LLP2A-Alendronate (LLP2A-Ale) that augments MSC homing to bone. The purpose of this study was to determine whether treatment with LLP2A-Ale or a combination of LLP2A-Ale and MSCs would accelerate bone healing in a mouse closed fracture model and if the effects are sex dependent. A right mid-femur fracture was induced in two-month-old osterix-mCherry (Osx-mCherry) male and female reporter mice. The mice were subsequently treated with placebo, LLP2A-Ale (500 μg/kg, IV), MSCs derived from wild-type female Osx-mCherry adipose tissue (ADSC, 3 x 105, IV) or ADSC + LLP2A-Ale. In phosphate buffered saline-treated mice, females had higher systemic and surface-based bone formation than males. However, male mice formed a larger callus and had higher volumetric bone mineral density and bone strength than females. LLP2A-Ale treatment increased exogenous MSC homing to the fracture gaps, enhanced incorporation of these cells into callus formation, and stimulated endochondral bone formation. Additionally, higher engraftment of exogenous MSCs in fracture gaps seemed to contribute to overall fracture healing and improved bone strength. These effects were sex-independent. There was a sex-difference in the rate of fracture healing. ADSC and LLP2A-Ale combination treatment was superior to on callus formation, which was independent of sex. Increased mobilization of exogenous MSCs to fracture sites accelerated endochondral bone formation and enhanced bone tissue regeneration. Stem Cells 2016;34:2587-2600.
authors.affiliation: Department of Internal Medicine, Center for Musculoskeletal Health, University of California at Davis Medical Center, Sacramento, California, USA. yao@ucdavis.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Internal Medicine, Center for Musculoskeletal Health, University of California at Davis Medical Center, Sacramento, California, USA.
authors.forename: Yu-An Evan
authors.initials: YE
authors.lastname: Lay
authors.affiliation: Department of Internal Medicine, Center for Musculoskeletal Health, University of California at Davis Medical Center, Sacramento, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kot
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California at Davis Medical Center, Sacramento, California, USA.
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Center for Musculoskeletal Health, University of California at Davis Medical Center, Sacramento, California, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Center for Musculoskeletal Health, University of California at Davis Medical Center, Sacramento, California, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California at Davis Medical Center, Sacramento, California, USA.
authors.forename: Kit
authors.initials: K
authors.lastname: Lam
authors.affiliation: Department of Internal Medicine, Center for Musculoskeletal Health, University of California at Davis Medical Center, Sacramento, California, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002146:Bony Callus / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D005264:Femoral Fractures / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D017102:Fracture Healing / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization; D007249:Inflammation / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology; D012727:Sex Characteristics
chemical_list: D004151:Dipeptides; C512274:LLP2A compound; D010671:Phenylurea Compounds; D019386:Alendronate
keywords: Adipose-derived stromal cells; Angiogenesis Osteogenesis; Bone-targeted; Fracture healing