An in vivo functional screen uncovers miR-150-mediated regulation of hematopoietic injury response.
An in vivo functional screen uncovers miR-150-mediated regulation of hematopoietic injury response.
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DOI：
10.1016/j.celrep.2012.09.014
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发表时间：
2012-10-25
期刊：
影响因子：
8.8
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Adams BD;Guo S;Bai H;Guo Y;Megyola CM;Cheng J;Heydari K;Xiao C;Reddy EP;Lu J
造血干细胞和造血祖细胞通常是化疗的不良靶点，导致造血抑制，需要仔细的临床处理。MicroRNAs是否控制造血损伤反应在很大程度上尚不清楚。我们报道了一种新的体内功能增强筛选和鉴定miR-150作为5-氟尿嘧啶诱导的损伤后的造血恢复的抑制物。利用带有条形码microRNA文库的骨髓移植模型，我们筛选了5-氟尿嘧啶治疗前后受体小鼠外周血中条形码的丰度。筛选候选miR-150的过度表达导致主要血系的恢复率显著减慢，并伴随着骨髓克隆形成能力的损害。相反，经5-氟尿嘧啶治疗后，来自miR-150缺失骨髓的血小板和髓系细胞恢复得更快。MiR-150的保守靶点c-myb杂合敲除，部分表型复制miR-150强制表达。我们的数据强调了microRNAs在控制造血损伤反应中的作用，并展示了在正常组织生理学中研究microRNAs的体内功能筛选的力量。
Hematopoietic stem and progenitor cells are often undesired targets of chemotherapies, leading to hematopoietic suppression requiring careful clinical management. Whether microRNAs control hematopoietic-injury response is largely unknown. We report a novel in vivo gain-of-function screen and identification of miR-150 as an inhibitor of hematopoietic recovery upon 5-fluorouracil-induced injury. Utilizing a bone marrow transplant model with a barcoded microRNA-library, we screened for barcode abundance in peripheral blood of recipient mice before and after 5-fluorouracil treatment. Overexpression of screen-candidate miR-150 resulted in significantly slowed recovery rates across major blood lineages, with associated impairment of bone marrow clonogenic potential. Conversely, platelets and myeloid cells from miR-150-null marrow recovered faster after 5-fluorouracil treatment. Heterozygous knockout of c-myb, a conserved target of miR-150, partially phenocopied miR-150 forced expression. Our data highlight the role of microRNAs in controlling hematopoietic-injury response, and demonstrate the power of in vivo functional screens for studying microRNAs in normal tissue physiology.
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