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. 2007 Feb 20;104(8):2750-5.
doi: 10.1073/pnas.0610983104. Epub 2007 Feb 9.

V体育官网 - CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control

Robert W Georgantas 3rd  1 , Richard Hildreth, Sebastien Morisot, Jonathan Alder, Chang-gong Liu, Shelly Heimfeld, George A Calin, Carlo M Croce, Curt I Civin
Affiliations

CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control

VSports在线直播 - Robert W Georgantas 3rd et al. Proc Natl Acad Sci U S A. .

Abstract

MicroRNAs (miRNAs) are a recently identified class of epigenetic elements consisting of small noncoding RNAs that bind to the 3' untranslated region of mRNAs and down-regulate their translation to protein. miRNAs play critical roles in many different cellular processes including metabolism, apoptosis, differentiation, and development. We found 33 miRNAs expressed in CD34+ hematopoietic stem-progenitor cells (HSPCs) from normal human bone marrow and mobilized human peripheral blood stem cell harvests. We then combined these data with human HSPC mRNA expression data and with miRNA-mRNA target predictions, into a previously undescribed miRNA:mRNA interaction database called the Transcriptome Interaction Database. The in silico predictions from the Transcriptome Interaction Database pointed to miRNA control of hematopoietic differentiation through translational control of mRNAs critical to hematopoiesis. From these predictions, we formulated a model for miRNA control of stages of hematopoiesis in which many of the genes specifying hematopoietic differentiation are expressed by HSPCs, but are held in check by miRNAs until differentiation occurs. We validated miRNA control of several of these target mRNAs by demonstrating that their translation in fact is decreased by miRNAs. Finally, we chose miRNA-155 for functional characterization in hematopoiesis, because we predicted that it would control both myelopoiesis and erythropoiesis VSports手机版. As predicted, miRNA-155 transduction greatly reduced both myeloid and erythroid colony formation of normal human HSPCs. .

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Conflict of interest statement (VSports注册入口)

Conflict of interest statement: The Johns Hopkins University holds patents on CD34 monoclonal antibodies and inventions related to stem cells. C. I. C. is entitled to a share of the sales royalty received by the university under licensing agreements between the university, Becton Dickinson Corp V体育安卓版. , and Baxter HealthCare Corp. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Figures (VSports注册入口)

Fig. 1.
Fig. 1.
A model for HE-miRNA-mediated control of human hematopoiesis. Determination and electronic annotation of the predicted target HSPC-expressed mRNAs for the HE-miRNAs yielded predictions of the differentiation stages where HE-miRNAs might block hematopoietic differentiation. Those HE-miRNAa shown in red are predicted to regulate hematopoiesis by our study and supported by other reports; those in orange are our additional predictions. The hierarchy of hematopoietic differentiation is that proposed by Kondo et al. (17). LT-HSC, long-term-repopulating HSC; ST-SHC, short-term-repopulating HSC; MPP, multipotent progenitor cell; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; GMP, granulocyte-macrophage progenitor; MEP, megakaryocyte-erythrocyte progenitor.
Fig. 2.
Fig. 2.
Translation of 16 of 18 tested hematopoietic differentiation-associated mRNAs is controlled by HE-miRNAs. Chimeric mRNAs, consisting of a luc reporter followed by the 3′ UTR from the mRNAs shown, were expressed in K562 cells from a CMV-driven plasmid construct. All values are the percent of luc expression as compared with the control plasmid construct containing luc only. Results are combined from four separate replicate experiments.
Fig. 3.
Fig. 3.
Deletion of specific predicted miRNA-binding sites restored translation of hematopoietic differentiation-associated mRNAs. Individual miRNA-binding sites were deleted from the luc-CXCR4 and luc-KLF2 chimeric mRNA constructs and then transfected into K562 cells. Labels show the mRNA name followed by the miRNA-binding site deleted from that 3′ UTR. All values are the percent of luc expression as compared with the plasmid construct containing luc only. Results are combined from four separate replicate experiments.
Fig. 4.
Fig. 4.
mir-155 inhibited generation of myeloid and erythroid colonies by normal primary human CD34+ cells. Normal PBSC CD34+ cells were transduced with FUGW (empty) or mir-155 lentivector. (A and B) Myeloid (A) and erythroid (B) colonies per 1,000 cells plated. (C) Representative colonies generated by control and mir-155-transduced cells. Results are representative of three separate experiments.
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