A Pig-a conditional knock-out mice model mediated by Vav-iCre: stable GPI-deficient and mild hemolysis.
A Pig-a conditional knock-out mice model mediated by Vav-iCre: stable GPI-deficient and mild hemolysis.
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Vav-iCre介导的Pig-a条件敲除小鼠模型：稳定的GPI缺陷和轻度溶血
DOI：
10.1186/s40164-022-00254-5
复制
发表时间：
2022-01-15
影响因子：
10.9
通讯作者：
Fu R
中科院分区：
文献类型：
--
作者：
Chen Y;Liu H;Zeng L;Li L;Lu D;Liu Z;Fu R
阵发性睡眠性血红蛋白尿是一种由造血干细胞PIG-A突变引起的克隆性疾病。目前尚无适合基础研究的PNH动物模型，因此迫切需要建立一种稳定的动物模型。我们利用ES靶向技术和Vav-ICRE建立了Pig-a条件性基因敲除小鼠模型。在CKO纯合子小鼠中，GPI和GPI-AP几乎完全缺失，且缺陷比例从出生起就保持稳定。在CKO杂合子小鼠中，GPI和GPI-AP缺陷的比例从出生起就部分缺失，并逐渐下降，直到出生后3个月达到稳定水平并保持终身。与正常C57BL/6N小鼠和Flox小鼠相比，CKO纯合子小鼠出现全血细胞减少，CKO杂合子小鼠出现白细胞减少和贫血。同时，CKO小鼠血清LDH、总胆红素、IBIL、补体C5b-9水平升高，血浆FHb浓度升高。在CKO小鼠的脾中更容易看到含铁血黄素颗粒细胞。此外，CKO小鼠具有稳定的转录特征。综上所述，我们的小鼠模型具有稳定的GPI缺陷和轻微的溶血，可能是一种理想的PNH体内实验模型。网上版载有补充材料，可在10.1186/s40164022-00254-5查阅。
Paroxysmal nocturnal hemoglobinuria is a clonal disease caused by PIG-A mutation of hematopoietic stem cells. At present, there is no suitable PNH animal model for basic research, therefore, it is urgent to establish a stable animal model. We constructed a Pig-a conditional knock-out mice model by ES targeting technique and Vav-iCre. The expressions of GPI and GPI-AP were almost completely absent in CKO homozygote mice, and the proportion of the deficiency remained stable from birth. In CKO heterozygote mice, the proportion of the deficiency of GPI and GPI-AP was partially absent and decreased gradually from birth until it reached a stable level at 3 months after birth and remained there for life. Compared with normal C57BL/6N mice and Flox mice, pancytopenia was found in CKO homozygous mice, and leukopenia and anemia were found in CKO heterozygotes mice. Meanwhile, in CKO mice, the serum LDH, TBIL, IBIL, complement C5b-9 levels were increased, and the concentration of plasma FHb was increased. Hemosiderin granulosa cells can be seen more easily in the spleens of CKO mice. What’s more, CKO mice had stable transcription characteristics. In conclusion, our mouse model has stable GPI-deficient and mild hemolysis, which may be an ideal in vivo experimental model for PNH. The online version contains supplementary material available at 10.1186/s40164-022-00254-5.
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DOI：
10.1038/nrdp.2017.28
发表时间：
2017-05-18
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Hill A;DeZern AE;Kinoshita T;Brodsky RA
通讯作者：
Brodsky RA
DOI：
10.1084/jem.194.5.581
发表时间：
2001-09-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Keller P;Payne JL;Tremml G;Greer PA;Gaboli M;Pandolfi PP;Bessler M
通讯作者：
Bessler M
影响因子：
20.3
作者：
Kawagoe, K;Kitamura, D;Takeda, J
通讯作者：
Takeda, J
影响因子：
15.9
作者：
Shen, Wenyi;Clemente, Michael J.;Makishima, Hideki
通讯作者：
Makishima, Hideki
影响因子：
2
作者：
Fraiman YS;Cuka N;Batista D;Vuica-Ross M;Moliterno AR
通讯作者：
Moliterno AR