Induced Pluripotent Stem Cells Expressing Elevated Levels of Sox-2, Oct-4, and Klf-4 Are Severely Reduced in Their Differentiation from Mesodermal to Hematopoietic Progenitor Cells
Induced Pluripotent Stem Cells Expressing Elevated Levels of Sox-2, Oct-4, and Klf-4 Are Severely Reduced in Their Differentiation from Mesodermal to Hematopoietic Progenitor Cells
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DOI：
10.1089/scd.2010.0391
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发表时间：
2011-07-01
影响因子：
4
通讯作者：
Tsuneto, Motokazu
中科院分区：
文献类型：
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作者：
Seiler, Katharina;Noghabi, Monireh Soroush;Tsuneto, Motokazu
通过异位表达Sox-2、Oct-4和Klf-4从骨髓（BM）造血祖细胞产生诱导多能干（iPS）细胞，由于它们的表观遗传记忆，希望它们可以比胚胎干（ES）细胞在体外更有效地分化成造血细胞谱系。体外培养系统已经标准化，以允许定量评估不同ES、BM衍生的iPS和成纤维细胞衍生的iPS细胞系发育为红系、髓系和淋巴细胞谱系的能力。令人惊讶的是，与ES细胞和成纤维细胞来源的iPS细胞相比，BM来源的iPS细胞体外分化为造血细胞的效率严重降低。BM衍生的iPS系的未分化以及分化阶段表达转录因子Sox-2、Oct-4和Klf-4的mRNA水平升高，iPS细胞已被这些转录因子转导。转录因子的过表达抑制Flk-1（+）中胚层向CD 45（+）造血祖细胞的发育。Sox-2的过表达似乎与造血潜能呈负相关。这些结果表明，以发育造血细胞为目的的iPS细胞生成应被控制并选择低水平的转导的Sox-2、Oct-4和Kfl-4表达。
Induced pluripotent stem (iPS) cells have been generated from bone marrow (BM) hematopoietic progenitor cells by ectopic expression of Sox-2, Oct-4, and Klf-4 with the hope that they may differentiate more efficiently than embryonic stem (ES) cells in vitro into hematopoietic cell lineages because of their epigenetic memory. An in vitro culture system has been standardized to allow a quantitative assessment of the capacities of different ES, BM-derived iPS, and fibroblast-derived iPS cell lines developing to erythroid, myeloid, and lymphoid cell lineages. Surprisingly, the efficiency to differentiate BM-derived iPS cells to hematopoietic cells in vitro is severely reduced compared with ES cells and fibroblast-derived iPS cells. Undifferentiated as well as differentiated stages of the BM-derived iPS lines express elevated mRNA levels of the transcription factors Sox-2, Oct-4, and Klf-4 with which the iPS cells have been transduced. Overexpression of the transcription factors inhibits development of Flk-1(+) mesodermal to CD45(+) hematopoietic progenitors. The overexpression of Sox-2 appears to be inversely related to hematogenic potency. These results suggest that iPS cell generation with the aim of developing hematopoietic cells should be controlled and selected for low levels of transduced Sox-2, Oct-4, and Kfl-4 expression.