[中文]最近,剑桥大学研究人员进行的一项小鼠研究表明,在早期胚胎中的异常细胞,并不一定表明出生婴儿有先天缺陷(如唐氏综合征)。3月29日在《Nature Communications》杂志上发表的一项研究中,科学家表明,异常细胞会被淘汰,取而代之的是健康细胞,从而修复胚胎——而且在许多情况下可完全修复。
剑桥大学生理学、发育学和神经科学系的研究人员,报道了一个非整倍性的小鼠模型,其胚胎中的一些细胞,包含异常数量的染色体。通常,人类胚胎中的每一个细胞应该包含23对染色体(22对染色体和1对性染色体),但一些细胞可能携带染色体的多个拷贝,这可能导致发育障碍。例如,有的孩子出生时有三个21号染色体的拷贝,他们将患上唐氏综合症。
孕妇——特别是大龄孕妇,其后代患这类疾病的风险最大,在产前检测中,可通过检测来预测基因异常的可能性。在怀孕11周和14周之间,母亲可能会接受次绒毛膜绒毛样检(CVS),这个测试包括,去除和分析来自胎盘的细胞。后面的测试,称为羊膜穿刺术,包括分析胎儿脱落到周围羊水中的细胞——这个测试更准确,但通常是在怀孕15周到20周期间进行的,此时胎儿正进一步发育。
这项研究的资深作者Zernicka-Goetz教授,在她孕育第二个孩子时受到自己经历的启发,开展了这项研究。Zernicka-Goetz教授说:“越来越多的女性生孩子的年龄在40岁以上,我就是其中一个,我孕育第二个孩子的时候44岁。”
当时,CVS测试发现,在连接她和胎儿的胎盘中,多达四分之一的细胞是异常的:发育中的胎儿也有异常细胞吗?当Zernicka-Goetz教授在与遗传学家讨论潜在影响时,她发现,关于发育胚胎内含有异常细胞的胚胎的命运,我们还了解甚少。
对Zernicka-Goetz教授来说,幸运的是,她的儿子Simon出生时很健康,她说:“我知道,当Simon健康出生时,我是多么幸运和快乐。”
Zernicka-Goetz教授补充说:“许多孕妇,不得不根据一次检测做出一个艰难的选择,而这些测试的结果我们并不完全理解。如果四分之一的胎盘细胞携带基因异常,意味着什么?孩子会有细胞异常的可能性有多大?这是我们想要回答的问题。既然女人生孩子的平均年龄不断上升,因此,这个问题就变得越来越重要。”
本文的另一位资深作者、惠康基金会Sanger研究所的Thierry Voet教授指出:“事实上,具有异常数量或异常结构染色体的异常细胞,曾在80 %到 90%的试管受精人类早期胚胎中观察到过,CSV测试可能一定程度地揭示了这些异常。”
在威康信托基金会资助的一项研究中,Zernicka-Goetz教授和他的同事,通过将8细胞阶段的小鼠胚胎——其中细胞是正常的,与细胞异常的胚胎进行混合,制备了一个非整倍性的小鼠模型。异常的小鼠胚胎相对来说不太常见,所以该研究团队使用一个称为逆转素(reversine)的分子,来诱发非整倍性。
在这种胚胎中——正常细胞和异常细胞各占一半,研究人员观察到,胚胎内的异常细胞被细胞凋亡(或程序性细胞死亡)杀死。这使得正常细胞接管过来,从而产生的胚胎其所有的细胞都是健康的。当细胞的混合是三个异常细胞与一个正常细胞时,一些不正常的细胞则继续生存,但是正常细胞的比例有所增加。
Zernicka-Goetz教授解释道:“胚胎有惊人的、修复自身的能力。我们发现,即使早期胚胎中有一半的细胞是异常的,胚胎也可能完全自我修复。如果在人类也是这样的话,这将意味着,即使初步迹象显示一个孩子可能有先天缺陷(因为其胚体中有一些异常细胞,但重要的是,并非所有的细胞都是异常的),事实情况可能未必如此。”
下一步,研究人员将试图确定,完全修复一个胚胎所需的健康细胞的确切比例,以及消除异常细胞的机制。[/中文]
[外文]Abnormal cells in the early embryo are not necessarily a sign that a baby will be born with a birth defect such as Down′s syndrome, suggests new research carried out in mice at the University of Cambridge. In a study published today in the journal Nature Communications, scientists show that abnormal cells are eliminated and replaced by healthy cells, repairing - and in many cases completely fixing - the embryo.
Researchers at the Department of Physiology, Development and Neuroscience at Cambridge report a mouse model of aneuploidy, where some cells in the embryo contain an abnormal number of chromosomes. Normally, each cell in the human embryo should contain 23 pairs of chromosomes (22 pairs of chromosomes and one pair of sex chromosomes), but some can carry multiple copies of chromosomes, which can lead of developmental disorders. For example, children born with three copies of chromosome 21 will develop Down′s syndrome.
Pregnant mothers - particular older mothers, whose offspring are at greatest risk of developing such disorders - are offered tests to predict the likelihood of genetic abnormalities. Between the 11th and 14th weeks of pregnancy, mothers may be offered chorionic villus sampling (CVS), a test that involves removing and analysing cells from the placenta. A later test, known as amniocentesis, involves analysing cells shed by the foetus into the surrounding amniotic fluid - this test is more accurate, but is usually carried out during weeks 15-20 of the pregnancy, when the foetus is further developed.
Professor Magdalena Zernicka-Goetz, the study′s senior author, was inspired to carry out the research following her own experience when pregnant with her second child. "I am one of the growing number of women having children over the age of 40 - I was pregnant with my second child when I was 44," says Professor Zernicka-Goetz.
At the time, a CVS test found that as many as a quarter of the cells in the placenta that joined her and her developing baby were abnormal: could the developing baby also have abnormal cells? When Professor Zernicka-Goetz spoke to geneticists about the potential implications, she found that very little was understood about the fate of embryos containing abnormal cells and about the fate of these abnormal cells within the developing embryos.
Fortunately for Professor Zernicka-Goetz, her son, Simon, was born healthy. "I know how lucky I was and how happy I felt when Simon was born healthy," she says.
"Many expectant mothers have to make a difficult choice about their pregnancy based on a test whose results we don′t fully understand," says Professor Zernicka-Goetz. "What does it mean if a quarter of the cells from the placenta carry a genetic abnormality - how likely is it that the child will have cells with this abnormality, too? This is the question we wanted to answer. Given that the average age at which women have their children is rising, this is a question that will become increasingly important."
"In fact, abnormal cells with numerical and/or structural anomalies of chromosomes have been observed in as many as 80-90% of human early stage embryos following in vitro fertilization," says Professor Thierry Voet from the Wellcome Trust Sanger Institute, UK, and the University of Leuven, Belgium, another senior author of this paper, "and CSV tests may expose some degree of these abnormalities."
In research funded by the Wellcome Trust, Professor Zernicka-Goetz and colleagues developed a mouse model of aneuploidy by mixing 8-cell stage mouse embryos in which the cells were normal with embryos in which the cells were abnormal. Abnormal mouse embryos are relatively unusual, so the team used a molecule known as reversine to induce aneuploidy.
In embryos where the mix of normal and abnormal cells was half and half, the researchers observed that the abnormal cells within the embryo were killed off by ′apoptosis′, or programmed-cell death, even when placental cells retained abnormalities. This allowed the normal cells to take over, resulting in an embryo where all the cells were healthy. When the mix of cells was three abnormal cells to one normal cell, some of abnormal cells continued to survive, but the ratio of normal cells increased.
"The embryo has an amazing ability to correct itself," explains Professor Zernicka-Goetz. "We found that even when half of the cells in the early stage embryo are abnormal, the embryo can fully repair itself. If this is the case in humans, too, it will mean that even when early indications suggest a child might have a birth defect because there are some, but importantly not all abnormal cells in its embryonic body, this isn′t necessarily the case."
The researchers will now try to determine the exact proportion of healthy cells needed to completely repair an embryo and the mechanism by which the abnormal cells are eliminated.[/外文]
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