Upregulating CXCR4 in Human Fetal Mesenchymal Stem Cells Enhances Engraftment and Bone Mechanics in a Mouse Model of Osteogenesis Imperfecta
Upregulating CXCR4 in Human Fetal Mesenchymal Stem Cells Enhances Engraftment and Bone Mechanics in a Mouse Model of Osteogenesis Imperfecta
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DOI：
10.5966/sctm.2011-0007
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发表时间：
2012-01-01
影响因子：
6
通讯作者：
Guillot, Pascale V.
中科院分区：
文献类型：
--
作者：
Jones, Gemma N.;Moschidou, Dafni;Guillot, Pascale V.
干细胞在修复受损器官和组织方面具有相当大的潜力。我们以前的研究表明，在小鼠成骨模型（oim小鼠）中产前移植人孕早期胎儿血间充质干细胞（hfMSCs）导致表型改善，骨折率显着降低。供体细胞分化为成熟的成骨细胞，产生骨蛋白和矿物质，包括I型胶原α 2，这在非移植小鼠中是缺乏的。这导致骨基质的修饰和随后的骨脆性的降低，表明移植的细胞直接有助于骨机械性能的改善。然而，由于骨植入水平有限，治疗效果不完全。在这项研究中，我们表明，虽然hfMSCs迁移到骨和骨髓是CXCR 4-SDF 1（SDF 1是基质衍生因子）依赖，只有少数细胞目前CXCR 4的细胞表面上，尽管高水平的内部CXCR 4。然而，用SDF 1引发上调CXCR 4以增加CXCR 4（+）细胞分数，改善体外趋化性并在oim和野生型骨和骨髓中增强体内植入至少三倍。在oim骨中较高的植入与骨脆性降低相关。这一策略代表了改善胎儿细胞疗法的治疗益处的一个步骤。干细胞翻译医学2012;1：70-78
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 I alpha 2, 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. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:70-78