Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis
Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis
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DOI：
10.1073/pnas.0802220105
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发表时间：
2008-09-02
影响因子：
11.1
通讯作者：
Tsuji, Kohichiro
中科院分区：
文献类型：
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作者：
Ma, Feng;Ebihara, Yasuhiro;Tsuji, Kohichiro
人类胚胎干细胞（hESC）临床应用的一个关键问题是它们能否产生具有正常功能的最终成熟后代。我们最近开发了一种通过与鼠胎肝源性基质细胞共培养从 hESC 高效生产造血祖细胞的方法。通过共培养产生的大量 hESC 衍生的红系祖细胞使我们能够在克隆水平上分析红细胞生成的发育并研究其功能。结果表明，各个克隆的红系细胞中珠蛋白的表达呈时间依赖性变化。特别是，在我们检查的所有克隆中，来自单个克隆的胚胎型表达 β 球蛋白的红系细胞减少，而表达成人型 β 球蛋白的细胞增加至接近 100%，这表明细胞经历了确定的造血作用。去核红细胞也出现在克隆后代中。比较分析表明，当检测糖蛋白A、CD71和CD81的表达时，hESC衍生的红系细胞与人脐带血CD34(+)祖细胞衍生的细胞采取相似的分化途径。此外，这些hESC衍生的红系细胞可以充当氧载体，并具有足够的葡萄糖-6-磷酸脱氢酶活性。本研究为探索人类红细胞生成和血红蛋白转换的早期发育提供了一个实验模型，并可能有助于发现治疗红细胞发育遗传性疾病的药物。
A critical issue for clinical utilization of human ES cells (hESCs) is whether they can generate terminally mature progenies with normal function. We recently developed a method for efficient production of hematopoietic progenitors from hESCs by coculture with murine fetal liver-derived stromal cells. Large numbers of hESCs-derived erythroid progenitors generated by the coculture enabled us to analyze the development of erythropoiesis at a clone level and investigate their function. The results showed that the globin expression in the erythroid cells in individual clones changed in a time-dependent manner. In particular, embryonic epsilon-globin-expressing erythroid cells from individual clones decreased, whereas adult-type beta-globin-expressing cells increased to approximate to 100% in all clones we examined, indicating that the cells undergo definitive hematopoiesis. Enucleated erythrocytes also appeared among the clonal progeny. A comparison analysis showed that hESC-derived erythroid cells took a similar differentiation pathway to human cord blood CD34(+) progenitor-derived cells when examined for the expression of glycophorin A, CD71 and CD81. Furthermore, these hESC-derived erythroid cells could function as oxygen carriers and had a sufficient glucose-6-phosphate dehydrogenase activity. The present study should provide an experimental model for exploring early development of human erythropoiesis and hemoglobin switching and may help in the discovery of drugs for hereditary diseases in erythrocyte development.