Regin Marius, Lei Yingnan, Couvreu De Deckersberg Edouard, Janssens Charlotte, Huyghebaert Anfien, Guns Yves, Verdyck Pieter, Verheyen Greta, Van de Velde Hilde, Sermon Karen, Spits Claudia
Brussels Health Campus/Faculty of Medicine and Pharmacy, Research Group Genetics Reproduction and Development, Vrije Universiteit Brussel, Brussels, Belgium.
Brussels Health Campus, Brussels IVF, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.
Elife. 2024 Dec 9;12:RP88916. doi: 10.7554/eLife.88916.
About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids showed that aneuploid cells are eliminated from the epiblast by p53-mediated apoptosis while being tolerated in the trophectoderm. These observations suggest a selective loss of aneuploid cells from human embryos, but the underlying mechanisms are not yet fully understood. Here, we investigated the cellular consequences of aneuploidy in a total of 125 human blastocysts. RNA-sequencing of trophectoderm cells showed activated p53 pathway and apoptosis proportionate to the level of chromosomal imbalance. Immunostaining corroborated that aneuploidy triggers proteotoxic stress, autophagy, p53-signaling, and apoptosis independent from DNA damage. Total cell numbers were lower in aneuploid embryos, due to a decline both in trophectoderm and in epiblast/primitive endoderm cell numbers. While lower cell numbers in trophectoderm may be attributed to apoptosis, aneuploidy impaired the second lineage segregation, particularly primitive endoderm formation. This might be reinforced by retention of NANOG. Our findings might explain why fully aneuploid embryos fail to further develop and we hypothesize that the same mechanisms lead to the removal of aneuploid cells from mosaic embryos.
约70%的人类卵裂期胚胎存在染色体嵌合现象，而在囊胚期这一比例降至20%。染色体嵌合的人类囊胚能够着床并生出核型正常的健康新生儿。对小鼠胚胎和人类原肠胚样结构的研究表明，非整倍体细胞在胚外滋养层中可被耐受，但会通过p53介导的细胞凋亡从外胚层中被清除。这些观察结果提示人类胚胎中非整倍体细胞存在选择性丢失，但其潜在机制尚未完全明确。在此，我们对总共125个人类囊胚中染色体非整倍性的细胞后果进行了研究。对滋养层细胞的RNA测序显示，p53通路激活以及细胞凋亡程度与染色体失衡水平成正比。免疫染色证实，非整倍性引发蛋白毒性应激、自噬、p53信号传导以及与DNA损伤无关的细胞凋亡。非整倍体胚胎中的细胞总数较少，这是由于滋养层以及外胚层/原始内胚层细胞数量均有所下降。虽然滋养层细胞数量减少可能归因于细胞凋亡，但非整倍性损害了第二次谱系分化，尤其是原始内胚层的形成。这可能因NANOG的保留而加剧。我们的研究结果或许可以解释为何完全非整倍体胚胎无法进一步发育，并且我们推测相同的机制导致了嵌合胚胎中非整倍体细胞的清除。
