The impact of aneuploidy on early human development

非整倍体对人类早期发育的影响

• 批准号: MR/X007979/1
• 负责人: Ivana Barbaric
• 金额: $ 120.78万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX007979%2F1
• 关键词: impact; aneuploidy; early; human; development

After fertilization, cells in the early embryo rapidly divide to produce the required cell numbers for building embryonic tissues. Such rapid cell divisions can be erroneous, resulting in cells with gains or losses of chromosomes, known as aneuploid cells. If aneuploid cells die off or if they are segregated to non-embryonic lineages (placenta), the embryo development may proceed normally. However, if aneuploid cells persist and proliferate, they may lead to developmental failure and pregnancy loss or, in some instances, the birth of a child with congenital abnormalities. Yet, we currently do not know what determines these different possible outcomes. Consequently, the detection of mosaic aneuploidy during prenatal testing presents a significant challenge for clinicians who have limited options in consulting the patients regarding the prognosis of pregnancy. Resolving this conundrum has been difficult as human embryos are experimentally inaccessible for obvious ethical reasons. In recent years, human pluripotent stem cells (hPSCs), which encompass cells derived from early human embryos and somatic cells reprogrammed to resemble early embryonic cells, have been used to model different stages of early human development. Through our previous work, we have collated a range of hPSCs with extra or missing chromosomes, resembling aneuploidies found in early embryos and chromosomal mosaicism syndromes, such as the Pallister-Killian syndrome. Utilising such lines, our goal here is to understand the consequences of aneuploidy and chromosomal mosaicism in early human development. To achieve this goal, our work will address the following outstanding questions:1) How does aneuploidy involving specific chromosomes affect early differentiation and patterning in in vitro models of human embryo development? 2) What is the outcome of interactions of diploid cells with aneuploid cells harbouring specific aneuploidies in models of mosaic embryos? 3) Which signalling pathways are dysregulated by aneuploidy and chromosomal mosaicism and can they be manipulated to promote aneuploid cell elimination?

受精后，早期胚胎中的细胞迅速分裂，产生构建胚胎组织所需的细胞数量。这种快速的细胞分裂可能是错误的，导致染色体增加或丢失的细胞，称为非整倍体细胞。如果非整倍体细胞死亡或分离到非胚胎血统(胎盘)，胚胎发育可能正常进行。然而，如果非整倍体细胞持续存在并增殖，它们可能会导致发育障碍和妊娠丢失，在某些情况下，可能会导致先天畸形儿童的出生。然而，我们目前不知道是什么决定了这些不同的可能结果。因此，在产前检查中检测马赛克非整倍体对临床医生来说是一个巨大的挑战，他们在咨询患者有关怀孕预后的问题上选择有限。解决这一难题一直很困难，因为出于明显的伦理原因，人类胚胎在实验上是无法获得的。近年来，人类多能干细胞(HPSCs)被用于模拟人类早期发育的不同阶段。hPSCs包括来自早期人类胚胎的细胞和重新编程为类似早期胚胎细胞的体细胞。通过我们之前的工作，我们已经整理了一系列具有额外或缺失染色体的hPSCs，类似于在早期胚胎中发现的非整倍体以及染色体嵌合体综合征，如Pallister-Killian综合征。利用这些品系，我们的目标是了解非整倍体和染色体嵌合体在人类早期发育中的后果。为了实现这一目标，我们的工作将解决以下突出问题：1)涉及特定染色体的非整倍体如何影响人类胚胎发育体外模型的早期分化和模式？2)在镶嵌胚胎模型中，二倍体细胞与含有特定非整倍体的非整倍体细胞相互作用的结果是什么？3)哪些信号通路受到非整倍体和染色体嵌合体的失调调控，它们能否被操纵以促进非整倍体细胞的消除？