Howard Hughes Medical Institute, Los Angeles, CA, USA.
Blood. 2011 Feb 17;117(7):2157-65. doi: 10.1182/blood-2010-08-302711. Epub 2010 Dec 16.
MicroRNAs (miRs) play an important role in cell differentiation and maintenance of cell identity, but relatively little is known of their functional role in modulating human hematopoietic lineage differentiation. Human embryonic stem cells (hESCs) provide a model system to study early human hematopoiesis. We differentiated hESCs by embryoid body (EB) formation and compared the miR expression profile of undifferentiated hESCs to CD34(+) EB cells. miRs-126/126* were the most enriched of the 7 miRs that were up-regulated in CD34(+) cells, and their expression paralleled the kinetics of hematopoietic transcription factors RUNX1, SCL, and PU.1. To define the role of miRs-126/126* in hematopoiesis, we created hESCs overexpressing doxycycline-regulated miRs-126/126* and analyzed their hematopoietic differentiation. Induction of miRs-126/126* during both EB differentiation and colony formation reduced the number of erythroid colonies, suggesting an inhibitory role of miRs-126/126* in erythropoiesis. Protein tyrosine phosphatase, nonreceptor type 9 (PTPN9), a protein tyrosine phosphatase that is required for growth and expansion of erythroid cells, is one target of miR-126. PTPN9 restoration partially relieved the suppressed erythropoiesis caused by miRs-126/126*. Our results define an important function of miRs-126/126* in negative regulation of erythropoiesis, providing the first evidence for a role of miR in hematopoietic differentiation of hESCs.
微小 RNA（miRs）在细胞分化和细胞特性维持中发挥着重要作用，但它们在调节人类造血谱系分化中的功能作用相对较少。人类胚胎干细胞（hESCs）为研究早期人类造血提供了一个模型系统。我们通过胚状体（EB）形成将 hESCs 分化，并将未分化的 hESCs 与 CD34（+）EB 细胞的 miR 表达谱进行比较。miR-126/126是 CD34（+）细胞中上调的 7 个 miR 中最丰富的 miR，其表达与造血转录因子 RUNX1、SCL 和 PU.1 的动力学平行。为了确定 miR-126/126在造血中的作用，我们创建了过表达强力霉素调控的 miR-126/126的 hESCs，并分析了它们的造血分化。在 EB 分化和集落形成过程中诱导 miR-126/126，会减少红系集落的数量，表明 miR-126/126在红细胞生成中起抑制作用。蛋白酪氨酸磷酸酶，非受体型 9（PTPN9），是红细胞生长和扩增所必需的一种蛋白酪氨酸磷酸酶，是 miR-126 的一个靶标。PTPN9 的恢复部分缓解了 miR-126/126引起的红细胞生成抑制。我们的结果定义了 miR-126/126*在负向调节红细胞生成中的重要功能，为 miR 在 hESCs 造血分化中的作用提供了第一个证据。
