Kit ligand has a critical role in mouse yolk sac and aorta-gonad-mesonephros hematopoiesis.
Kit ligand has a critical role in mouse yolk sac and aorta-gonad-mesonephros hematopoiesis.
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DOI：
10.15252/embr.201745477
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发表时间：
2018-10
期刊：
影响因子：
7.7
通讯作者：
de Bruijn MF
中科院分区：
文献类型：
--
作者：
Azzoni E;Frontera V;McGrath KE;Harman J;Carrelha J;Nerlov C;Palis J;Jacobsen SEW;de Bruijn MF
很少有研究报道哺乳动物胚胎对造血细胞生态位因子的体内需求。在这里，我们全面分析了卵黄囊和腹主动脉-性腺-中肾(AGM)壁龛对Kit配体(Kitl)的需求。对功能丧失和转基因报告鼠模型的深入分析表明，Kitl缺陷胚胎的卵黄囊红髓祖细胞(EMP)数量减少，这是由于它们最初出现的增殖缺陷所致。这种电磁脉冲缺陷导致在造血干细胞(HSC)来源的红细胞生成开始之前胎肝红系细胞急剧减少，并导致组织驻留巨噬细胞减少。AGM中的前HSCs需要Kitl才能存活和成熟，但不需要增殖。尽管Kit1广泛表达于所有胚胎的造血龛中，但内皮细胞的条件性缺失重现了AGM和卵黄囊中胚系功能丧失的表型，当迁移到胎肝时，表型的HSCs而不是EMPs仍然依赖于内皮Kit1。总之，我们的数据证实Kitl在体内AGM和卵黄囊内皮细胞生态位中是一个关键的调节因子。
Few studies report on the in vivo requirement for hematopoietic niche factors in the mammalian embryo. Here, we comprehensively analyze the requirement for Kit ligand (Kitl) in the yolk sac and aorta–gonad–mesonephros (AGM) niche. In‐depth analysis of loss‐of‐function and transgenic reporter mouse models show that Kitl‐deficient embryos harbor decreased numbers of yolk sac erythro‐myeloid progenitor (EMP) cells, resulting from a proliferation defect following their initial emergence. This EMP defect causes a dramatic decrease in fetal liver erythroid cells prior to the onset of hematopoietic stem cell (HSC)‐derived erythropoiesis, and a reduction in tissue‐resident macrophages. Pre‐HSCs in the AGM require Kitl for survival and maturation, but not proliferation. Although Kitl is expressed widely in all embryonic hematopoietic niches, conditional deletion in endothelial cells recapitulates germline loss‐of‐function phenotypes in AGM and yolk sac, with phenotypic HSCs but not EMPs remaining dependent on endothelial Kitl upon migration to the fetal liver. In conclusion, our data establish Kitl as a critical regulator in the in vivo AGM and yolk sac endothelial niche.