Therapeutic potential of genetically modified adult stem cells for osteopenia.
Therapeutic potential of genetically modified adult stem cells for osteopenia.
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成体干细胞具有治疗潜力，因为它们具有自我更新的内在能力，特别是用于骨再生。本研究证明了体外修饰的间充质干细胞（MSC）的效用，以提高骨质疏松症的免疫活性小鼠模型的骨密度。用重组腺相关病毒2（rAAV）在胶原蛋白1α启动子的转录控制下表达BMP-2，体外转导MSC。为了丰富体内骨归巢，进一步修饰细胞以瞬时表达小鼠α-4整联蛋白。将修饰的MSC全身施用给卵巢切除的雌性C57 BL/6小鼠。治疗效果通过双能X线吸收测定法、3D显微CT、组织学和免疫组织化学进行了长达6个月的测定。结果表明，与对照动物相比，移植有表达BMP-2的MSC的小鼠显示出骨矿物质密度和骨矿物质含量的显著增加（p<0.001），具有相对更好的骨髓基质细胞增殖能力和更高的成骨细胞池。股骨的显微CT分析和其他骨组织形态计量学分析表明，MSC-BMP-2治疗后有更多的松质骨。通过移植来自GFP转基因小鼠的遗传修饰的MSC获得的结果表明，来自移植的MSC的BMP 2的产生也影响用于新骨形成的内源性祖细胞的动员。
Adult stem cells have therapeutic potential because of their intrinsic capacity for self-renewal, especially for bone regeneration. The present study demonstrates the utility of ex vivo modified mesenchymal stem cells (MSC) to enhance bone density in an immunocompetent mouse model of osteopenia. MSC were transduced ex vivo with a recombinant adeno-associated virus 2 (rAAV) expressing BMP-2 under the transcriptional control of collagen type-1α promoter. To enrich bone homing in vivo, the cells were further modified to transiently express the mouse α-4 integrin. The modified MSC were systemically administered to ovariectomized, female C57BL/6 mice. Effects of the therapy were determined by dual energy x-ray absorptiometry, 3D micro-CT, histology, and immunohistochemistry for up to six months. Results indicated that mice transplanted with MSC expressing BMP-2 showed significant increase in bone mineral density and bone mineral content(p<0.001) with relatively better proliferative capabilities of bone marrow stromal cells and higher osteocompetent pool of cells compared to control animals. Micro-CT analysis of femora and other bone histomorphometric analyses indicated more trabecular bone following MSC-BMP-2 therapy. Results obtained by transplanting genetically modified MSC from GFP transgenic mouse suggested that production of BMP2 from transplanted MSC also influenced the mobilization of endogenous progenitors for new bone formation.
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