The Impact of Integrin 2 on Granulocyte/Macrophage Progenitor Proliferation
The Impact of Integrin 2 on Granulocyte/Macrophage Progenitor Proliferation
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整合素 2 对粒细胞/巨噬细胞祖细胞增殖的影响
DOI：
10.1002/stem.2961
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发表时间：
2019-03-01
期刊：
影响因子：
5.2
通讯作者：
Feng, Ying-Mei
中科院分区：
文献类型：
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作者：
Zhang, Li-Jie;Yan, Cen;Feng, Ying-Mei
之前，我们报道了尽管2-/-和2+/+小鼠骨髓细胞（BMC）中的HSPC频率相当，但将2-/- BMC移植到致死性照射的CD45.1受体中导致比2+/+ BMC更多的髓样细胞产生。本研究的目的是解决如果整合素2缺乏扭曲粒细胞/巨噬细胞祖细胞（GMP）增殖。流式细胞仪分析表明，GMP频率和细胞数较高，巨核细胞/红细胞祖细胞的频率和细胞数较低，在2-/-小鼠比2+/+小鼠。然而，两组之间的共同髓系祖细胞（CMP）频率和细胞数量相似。GMP数量的增加是由于GMP增殖，如BrdU掺入GMP的百分比所证明的。全基因组转录组分析鉴定了与2+/+ CMP相比，2-/- CMP中Fc ε RI表达增加。通过qRT-PCR和流式细胞仪检测到2-/-小鼠中2-/- GMP上的Fc RI epsilon表达增加。尽管Fc γ RIhi GMP或Fc γ RIlo GMP移植到致死性照射的CD45.1受体中导致相当的髓样细胞产生，但2缺陷Fc γ RIhi GMP的移植比2+/+ Fc γ RIhi GMP产生更多的髓样细胞。2-/- GMP中GATA 2表达增加。使用荧光素酶报告基因分析，我们证明了Fc ε RI启动子区域中GATA 2结合位点的突变减少了Fc ε RI转录。在体外，添加IgE，Fc β RI的配体，促进GMP扩增，这是废除抑制JNK磷酸化。整合素2缺陷促进GMP增殖和髓样细胞生成，这是通过Fc β RI/IgE诱导GMP中JNK磷酸化介导的。干细胞2019;37：430-440
Previously, we reported that although the HSPC frequency in bone marrow cells (BMC) was comparable between 2-/- and 2+/+ mice, transplantation of 2-/- BMC into lethally irradiated CD45.1 recipient resulted in more myeloid cell production than 2+/+ BMC. The objective of this study is to address if integrin 2 deficiency skews granulocyte/macrophage progenitor (GMP) proliferation. FACS analysis demonstrated that GMP frequency and cell number were higher and megakaryocyte/erythrocyte progenitor frequency and cell number were lower in 2-/- mice than 2+/+ mice. However, the common myeloid progenitors (CMP) frequency and cell number were similar between the two groups. The increased GMP number was due to GMP proliferation as evidenced by the percentage of BrdU-incorporating GMP. Whole genome transcriptome analysis identified increased Fc epsilon RI expression in 2-/- CMP compared to 2+/+ CMP. Fc epsilon RI expression on 2-/- GMP was detected increased in 2-/- mice by qRT-PCR and FACS. Although transplantation of Fc epsilon RIhi GMP or Fc epsilon RIlo GMP into lethally irradiated CD45.1 recipient resulted in comparable myeloid cell production, transplantation of 2 deficient Fc epsilon RIhi GMP generated more myeloid cells than 2+/+ Fc epsilon RIhi GMP. GATA2 expression was increased in 2-/- GMP. Using a luciferase reporter assay, we demonstrated that mutation of the GATA2 binding site in the Fc epsilon RI promoter region diminished Fc epsilon RI transcription. In vitro, the addition of IgE, the ligand of Fc epsilon RI, promoted GMP expansion, which was abrogated by inhibition of JNK phosphorylation. Integrin 2 deficiency promoted GMP proliferation and myeloid cell production, which was mediated via Fc epsilon RI/IgE-induced JNK phosphorylation in GMP. Stem Cells2019;37:430-440