Laboratory of Experimental Hematology, Institute for Medical Research, University of Belgrade, Belgrade, 11129, Serbia.
J Transl Med. 2012 Jun 7;10:116. doi: 10.1186/1479-5876-10-116.
It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival have also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34+ progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny.
Hematopoietic CD34+ progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells.
In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS2, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes are differentially expressed only in some stages of ontogeny (STATs, GRB2, CREBB). Beside the continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression (NFKBIA, YWHAH).
This broad overview of gene expression in erythropoiesis revealed transcription factors differentially expressed in some stages of ontogenesis. Finally, our results show that EPO-mediated proliferation and survival of erythroid progenitors occurs mainly through modulation of JAK-STAT pathway associated STATs, GRB2 and PIK3 genes, as well as AKT pathway-coupled NFKBIA and YWHAH genes.
已有报道称，磷脂酰肌醇 3-激酶（PI3K）-AKT 信号通路调节促红细胞生成素（EPO）诱导的早期红细胞祖细胞的存活、增殖和成熟。红细胞的增殖和存活也与 JAK-STAT 通路的激活有关。本研究的目的是观察 EPO 激活 JAK-STAT 和 PI3K/AKT 通路在造血 CD34+祖细胞向红细胞祖细胞发育中的作用，并区分人类红细胞祖细胞在个体发生过程中的早期 EPO 靶基因。
从胎儿和成人造血组织中分离造血 CD34+祖细胞，将其分化为红细胞祖细胞。我们使用微阵列分析来检查 JAK-STAT 和 PI3K/AKT 相关基因，以及这些人类红细胞祖细胞中广泛的基因表达调节。
在微阵列研究中，胎肝中表达了 1755 个基因，脐血中表达了 3844 个基因，成人骨髓中表达了 1770 个基因，外周血衍生的红细胞祖细胞中表达了 1325 个基因。红细胞祖细胞共有 1011 个共同基因。使用 Ingenuity 通路分析软件，我们评估了与血液系统发育、细胞生长和增殖相关的基因的网络通路。KITLG、EPO、GATA1、PIM1 和 STAT3 基因代表与血液系统发育相关基因的主要连接点。一些 JAK-STAT 信号通路相关基因在整个个体发生过程中持续上调（PIM1、SOCS2、MYC、PTPN11），而其他基因则下调（PTPN6、PIAS、SPRED2）。此外，一些 JAK-STAT 通路相关基因仅在个体发生的某些阶段表达差异（STATs、GRB2、CREBB）。除了在 PI3K-AKT 信号通路中持续上调（AKT1、PPP2CA、CHUK、NFKB1）和下调（FOXO1、PDPK1、PIK3CG）的基因外，我们还观察到间歇性调节的基因表达（NFKBIA、YWHAH）。
本研究广泛概述了红细胞生成过程中的基因表达，揭示了在个体发生的某些阶段表达差异的转录因子。最后，我们的结果表明，EPO 介导的红细胞祖细胞增殖和存活主要通过调节 JAK-STAT 通路相关的 STATs、GRB2 和 PIK3 基因，以及 AKT 通路偶联的 NFKBIA 和 YWHAH 基因来实现。
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