Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade.
Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade.
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DOI：
10.1038/s41467-022-32171-w
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发表时间：
2022-07-29
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
胎儿生长受限（FGR）影响5-10%的怀孕，并可能对母亲和孩子造成严重后果。由于对FGR的发病机制知之甚少，预防和治疗受到限制。遗传学研究表明KIR和HLA基因与FGR有关，然而，连锁不平衡，父母双方的遗传影响以及调查人类妊娠的挑战使得风险等位基因及其功能影响难以定位。在这里，我们证明了在子宫自然杀伤（NK）细胞上表达的母体KIR 2DL 1和在胎儿滋养层细胞上表达的父系遗传的HLA-C*0501之间的相互作用，导致人源化小鼠模型中的FGR。我们发现KIR 2DL 1和C*0501的相互作用导致致病性子宫动脉重塑和子宫NK细胞功能的调节。这种初始效应级联改变母胎界面的转录表达和细胞间通讯。这些发现提供了对特定FGR风险等位基因的机制见解，并提供了预防和治疗的途径。自然杀伤细胞调节胎儿生长。在这里，作者使用人源化转基因小鼠来证明特异性HLA-C KIR 2DL相互作用促进母体和胎儿细胞转录组的变化，导致胎盘血管系统、细胞间通讯和胎儿生长限制的改变。
Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment. Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.
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影响因子：
15.3
作者：
Ashkar, A A;Di Santo, J P;Croy, B A
通讯作者：
Croy, B A
DOI：
10.1073/pnas.95.11.6355
发表时间：
1998-05-26
影响因子：
11.1
作者：
Babic, AM;Kireeva, ML;Lau, LF
通讯作者：
Lau, LF
影响因子：
4.5
作者：
Dey, Kushal K.;Hsiao, Chiaowen Joyce;Stephens, Matthew
通讯作者：
Stephens, Matthew
影响因子：
3.7
作者：
Chen CM;Krohn J;Bhattacharya S;Davies B
通讯作者：
Davies B
DOI：
10.1088/1742-5468/2008/10/p10008
发表时间：
2008-10-01
影响因子：
2.4
作者：
Blondel, Vincent D.;Guillaume, Jean-Loup;Lefebvre, Etienne
通讯作者：
Lefebvre, Etienne