Therapeutic effects of induced pluripotent stem cells in chimeric mice with β-thalassemia
Therapeutic effects of induced pluripotent stem cells in chimeric mice with β-thalassemia
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诱导多能干细胞对β地中海贫血嵌合小鼠的治疗作用
DOI：
10.3324/haematol.2013.087916
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发表时间：
2014-08-01
期刊：
影响因子：
10.1
通讯作者：
Zeng, Fanyi
中科院分区：
文献类型：
--
作者：
Yang, Guanheng;Shi, Wansheng;Zeng, Fanyi
虽然β-地中海贫血是人类最常见的遗传病之一，但除了骨髓移植外，目前仍没有有效的治疗方法。诱导多能干细胞被认为是未来修复或替换功能不全的器官的良好候选者。为了开发针对地中海贫血的转基因诱导多能干细胞疗法，从转正常人β-珠蛋白基因的β(654)地中海贫血小鼠中诱导出多能干细胞，并将其与表达红系的报告基因GFP一起用于产生嵌合体小鼠。使用这些嵌合体模型，我们研究了包括血液学参数和组织病理学在内的各种病理指标的变化。我们的数据显示，当贝塔(654)诱导的多能干细胞与正常人类贝塔珠蛋白基因在贝塔(654)小鼠中的嵌合率超过30%时，贫血的病理似乎是逆转的，而8%到16%的嵌合率对典型的贝塔-地中海贫血表型几乎没有改善。当诱导的拥有红系表达报告GFP的多能干细胞在Beta(654)小鼠中的嵌合率大于10%时，观察到有效地缓解了地中海贫血相关的表型。因此，在我们的β-地中海贫血小鼠模型中，10%或更多的外源性正常β-珠蛋白基因的表达可以降低贫血的程度，而具有正常人类β-珠蛋白基因的β(654)诱导的多能干细胞治疗有稳定的治疗效果，但更具剂量依赖性。
Although beta-thalassemia is one of the most common human genetic diseases, there is still no effective treatment other than bone marrow transplantation. Induced pluripotent stem cells have been considered good candidates for the future repair or replacement of malfunctioning organs. As a basis for developing transgenic induced pluripotent stem cell therapies for thalassemia, beta(654) induced pluripotent stem cells from a beta(654)-thalassemia mouse transduced with the normal human beta-globin gene, and the induced pluripotent stem cells with an erythroid-expressing reporter GFP were used to produce chimeric mice. Using these chimera models, we investigated changes in various pathological indices including hematologic parameters and tissue pathology. Our data showed that when the chimerism of beta(654) induced pluripotent stem cells with the normal human beta-globin gene in beta(654) mice is over 30%, the pathology of anemia appeared to be reversed, while chimerism ranging from 8% to 16% provided little improvement in the typical beta-thalassemia phenotype. Effective alleviation of thalassemia-related phenotypes was observed when chimerism with the induced pluripotent stem cells owning the erythroid-expressing reporter GFP in beta(654) mouse was greater than 10%. Thus, 10% or more expression of the exogenous normal beta-globin gene reduces the degree of anemia in our beta-thalassemia mouse model, whereas treatment with beta(654) induced pluripotent stem cells which had the normal human beta-globin gene had stable therapeutic effects but in a more dose-dependent manner.