MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets
MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets
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DOI：
10.1073/pnas.1016218107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Park, Christopher Y.
中科院分区：
文献类型：
--
作者：
Ooi, A. G. Lisa;Sahoo, Debashis;Park, Christopher Y.
MicroRNA通过调节祖细胞命运决定以及成熟的免疫效应子功能而深刻地影响造血细胞。然而，迄今为止，调节造血干细胞（HSC）功能的microRNA的特征还不太清楚。在这里，我们发现microRNA-125 b（miR-125 b）在HSC中高度表达，而在定向祖细胞中表达减少。小鼠HSC中miR-125 b的过表达增强了它们的功能，通过高度纯化的HSC的连续移植证实，并富集了先前描述的多能HSC（CD 34-KLS）组分中的Slamf（lo）CD 34（-）淋巴平衡和Slamf 1（neg）CD 34（-）淋巴偏向的细胞亚群。来源于miR-125 b过表达HSC的成熟外周血细胞倾向于淋巴系。与这一观察结果一致，miR-125 b过表达显著增加脾脏内早期B祖细胞的数量，并通过抗凋亡机制诱导淋巴平衡和淋巴偏向的HSC亚群的扩增和富集，降低两种促凋亡靶点Bmf和KLF 13的mRNA表达水平。miR-125 b的抗凋亡作用在淋巴偏向的HSC亚群中更明显，因为它们固有的更高的凋亡基线水平。miR-125 b的这些作用与淋巴组织增生性疾病的发生相关，以CD 8（+）T淋巴细胞的扩增为标志。综上所述，这些数据揭示了miR-125 b调节HSC存活，并且可以通过优先扩增淋巴平衡和淋巴偏向的HSC在HSC水平上促进淋巴命运决定。
MicroRNAs profoundly impact hematopoietic cells by regulating progenitor cell-fate decisions, as well as mature immune effector function. However to date, microRNAs that regulate hematopoietic stem cell (HSC) function have been less well characterized. Here we show that microRNA-125b (miR-125b) is highly expressed in HSCs and its expression decreases in committed progenitors. Overexpression of miR-125b in mouse HSC enhances their function, demonstrated through serial transplantation of highly purified HSC, and enriches for the previously described Slamf(lo)CD34(-) lymphoid-balanced and the Slamf1(neg)CD34(-) lymphoid-biased cell subsets within the multipotent HSC (CD34-KLS) fraction. Mature peripheral blood cells derived from the miR-125b-overexpressing HSC are skewed toward the lymphoid lineage. Consistent with this observation, miR-125b overexpression significantly increases the number of early B-progenitor cells within the spleen and induces the expansion and enrichment of the lymphoid-balanced and lymphoid-biased HSC subset via an antiapoptotic mechanism, reducing the mRNA expression levels of two proapoptotic targets, Bmf and KLF13. The antiapoptotic effect of miR-125b is more pronounced in the lymphoid-biased HSC subset because of their intrinsic higher baseline levels of apoptosis. These effects of miR-125b are associated with the development of lymphoproliferative disease, marked by expansion of CD8(+) T lymphocytes. Taken together, these data reveal that miR-125b regulates HSC survival and can promote lymphoid-fate decisions at the level of the HSC by preferentially expanding lymphoid-balanced and lymphoid-biased HSC.