Yao Wei, Lay Yu-An Evan, Kot Alexander, Liu Ruiwu, Zhang Hongliang, Chen Haiyan, Lam Kit, Lane Nancy E
Department of Internal Medicine, Center for Musculoskeletal Health, University of California at Davis Medical Center, Sacramento, California, USA.
Department of Biochemistry and Molecular Medicine, University of California at Davis Medical Center, Sacramento, California, USA.
Stem Cells. 2016 Oct;34(10):2587-2600. doi: 10.1002/stem.2433. Epub 2016 Jul 15.
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 10 , 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.
间充质干细胞（MSC）移植已在动物和临床骨折研究中进行了测试。我们开发了一种趋骨性化合物，LLP2A-阿仑膦酸盐（LLP2A-Ale），它可增强MSC归巢至骨。本研究的目的是确定用LLP2A-Ale或LLP2A-Ale与MSC联合治疗是否会加速小鼠闭合性骨折模型中的骨愈合，以及这些效果是否存在性别差异。在两个月大的osterix-红色荧光蛋白（Osx-红色荧光蛋白）雄性和雌性报告基因小鼠中诱导右股骨中段骨折。随后，小鼠接受安慰剂、LLP2A-Ale（500μg/kg，静脉注射）、源自野生型雌性Osx-红色荧光蛋白脂肪组织的MSC（脂肪来源干细胞，3×10，静脉注射）或脂肪来源干细胞+LLP2A-Ale治疗。在磷酸盐缓冲盐水处理的小鼠中，雌性的全身和基于表面的骨形成高于雄性。然而，雄性小鼠形成的骨痂更大，体积骨矿物质密度和骨强度高于雌性。LLP2A-Ale治疗增加了外源性MSC归巢至骨折间隙，增强了这些细胞在骨痂形成中的掺入，并刺激了软骨内骨形成。此外，外源性MSC在骨折间隙中更高的植入似乎有助于整体骨折愈合并改善骨强度。这些效果与性别无关。骨折愈合速率存在性别差异。脂肪来源干细胞和LLP2A-Ale联合治疗在骨痂形成方面优于单一治疗，且与性别无关。外源性MSC向骨折部位的动员增加加速了软骨内骨形成并增强了骨组织再生。《干细胞》2016年；34：2587 - 2600。
