Maturation-associated gene expression profiles during normal human bone marrow erythropoiesis
Maturation-associated gene expression profiles during normal human bone marrow erythropoiesis
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DOI：
10.1038/s41420-019-0151-0
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发表时间：
2019-02-28
影响因子：
7
通讯作者：
Orfao, Alberto
中科院分区：
文献类型：
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作者：
Mello, Fabiana, V;Land, Marcelo G. P.;Orfao, Alberto
红细胞生成已使用体外和体内动物模型进行了广泛研究。尽管如此，关于原代（离体）正常人骨髓（BM）红系成熟的基因表达谱（GEP）的数据仍然有限。我们研究了正常人骨髓红细胞生成期间有核红细胞 (NRBC) 前体的 GEP。通过流式细胞术从（新鲜）正常人骨髓中鉴定和纯化了三个与成熟相关的 NRBC 群体，并使用 DNA 寡核苷酸微阵列直接分析每个纯化细胞群体的 GEP。总体而言，6569个基因（所研究的基因的19％）在BM红细胞生成的> = 1阶段中以稳定（例如，涉及DNA过程、细胞信号传导、蛋白质组织和血红蛋白产生的基因）或可变量（例如，与细胞分化、凋亡、代谢相关的基因）表达，后者表现出从1阶段到3阶段（与红细胞分化和存活调节相关的基因，例如， SPI1、STAT5A）或从第 2 阶段增加到第 3 阶段（与自噬、红细胞功能（例如血红素生成，例如 ALAS1、ALAS2）、铁代谢（例如 ISCA1、SLC11A2）、氧化应激保护（例如 UCP2、PARK7）和 NRBC 去核（例如 ID2、RB1）相关的基因。有趣的是，参与细胞凋亡（例如 CASP8、P2RX1）和免疫反应（例如 FOXO3、TRAF6）的基因在 NRBC 前体成熟的最后阶段（第 3 阶段）也不受调节。我们的结果证实并扩展了之前的观察结果，并为更好地理解人类红细胞成熟的关键步骤及其在不同克隆和非克隆红细胞生成障碍患者中的潜在变化提供了参考框架。
Erythropoiesis has been extensively studied using in vitro and in vivo animal models. Despite this, there is still limited data about the gene expression profiles (GEP) of primary (ex vivo) normal human bone marrow (BM) erythroid maturation. We investigated the GEP of nucleated red blood cell (NRBC) precursors during normal human BM erythropoiesis. Three maturation-associated populations of NRBC were identified and purified from (fresh) normal human BM by flow cytometry and the GEP of each purified cell population directly analyzed using DNA oligonucleotide microarrays. Overall, 6569 genes (19% of the genes investigated) were expressed in >= 1 stage of BM erythropoiesis at stable (e.g., genes involved in DNA process, cell signaling, protein organization and hemoglobin production) or variable amounts (e.g., genes related to cell differentiation, apoptosis, metabolism), the latter showing a tendency to either decrease from stage 1 to 3 (genes associated with regulation of erythroid differentiation and survival, e.g., SPI1, STAT5A) or increase from stage 2 to stage 3 (genes associated with autophagy, erythroid functions such as heme production, e.g., ALAS1, ALAS2), iron metabolism (e.g., ISCA1, SLC11A2), protection from oxidative stress (e.g., UCP2, PARK7), and NRBC enucleation (e.g., ID2, RB1). Interestingly, genes involved in apoptosis (e.g., CASP8, P2RX1) and immune response (e.g., FOXO3, TRAF6) were also unregulated in the last stage (stage 3) of maturation of NRBC precursors. Our results confirm and extend on previous observations and providing a frame of reference for better understanding the critical steps of human erythroid maturation and its potential alteration in patients with different clonal and non-clonal erythropoietic disorders.