Abnormalities in centrosome number in human embryos and embryonic stem cells

Abstract

Chromosomal abnormalities are common in human embryos. Previous studies have suggested links between centrosome number and chromosome abnormalities, but information regarding abnormalities in centrosome number in human embryos is limited. We analyzed abnormalities in centrosome number in human embryos and embryonic stem cells (hESCs). Following normal fertilization, supernumerary centrosomes were present at rates of 7.3% in two-pronucleus (2PN)-stage zygotes and 6.5% in first-cleavage zygotes. Supernumerary centrosomes were also detected in 24.4% of blastomeres from 60% of embryos derived from 2PN zygotes. Conversely, in mono- (1PN) and tri-pronucleus (3PN) zygotes, the frequency of abnormal centrosome number increased substantially at first cleavage. Rates in blastomeres of Day-3 embryos, however, were about the same between embryos derived from 1PN and 2PN zygotes, whereas abnormalities in centrosome number were higher in those from 3PN zygotes. By comparison, the rate of abnormal centrosome numbers in hESCs was 1.5-11.2%. Thus, abnormalities in centrosome number existed in human zygotes and cleaved embryos-especially those resulting from aberrant fertilization-but the frequency of such abnormalities was lower in hESCs derived from these embryos. These findings identify a source of the chromosomal instability in human embryos and hESCs, and highlight new safety issues for human assisted reproductive technology. Mol. Reprod. Dev. 83: 392-404, 2016. © 2016 Wiley Periodicals, Inc.

Mechanism of spindle pole organization and instability in human oocytes

“…Furthermore, although most human oocytes with unstable spindles show lagging chromosomes during anaphase ( 2 ), only a fraction of lagging chromosomes will eventually lead to aneuploidy ( 125 ). Spindle instability also appears to occur more frequently in meiosis I than in meiosis II and the first mitotic division ( 2 , 11 – 13 , 126 ). This could be because of additional differences in the spindle architecture and the process of spindle assembly.…”

“…The deficiency of KIFC1 may also render zygotic spindles unstable. Human zygotes have low levels of KIFC1 mRNA and a high incidence of multipolar spindles (9)(10)(11)(12)(13). Spindles are, however, mostly bipolar in human two-cellstage embryos (13).…”

“…However, the causes of spindle instability in human oocytes are still unknown. Also, human fertilized eggs (zygotes) are prone to assembling multipolar spindles and undergo multipolar divisions (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Identifying the causes of spindle instability may lead to therapeutic strategies that reduce chromosome segregation errors in human eggs and improve outcomes of assisted reproductive technology.…”

A Multilevel Approach to the Causes of Genetic Instability in Stem Cells

“…There are three main causes for genetic alterations in IPSCs: progenitor cells with preexisting mutations, DNA changes that arise during reprogramming, and those mutations that appears de novo during proliferation in culture (Tichy 2011). There are another causes of aneuploidy like supernumerary centrosomes that are often found in hESCs derived from human zygotes and cleaved embryos that aroused from disturbed fertilization, characteristically, the proportion of hESCs bearing the anomalies is lower than that in their earlier progenitor (Gu et al 2016).…”

Maternal common variant rs2305957 spanning PLK4 is associated with blastocyst formation and early recurrent miscarriage

“…Despite extensive investigation, little is known about the complex origins and mechanisms underlying aneuploidy. Although most studies support the considerable role of oocyte meiotic-origin error in aneuploidy formation, accumulated evidence has highlighted the importance of post-zygotic mitotic-origin aneuploidy in reproductive losses (13,14). The phenomenon that aneuploidy incidences differ even among age-similar women indicates that parental genome variants may be involved in aneuploidy formation and account for variations in aneuploidy rates occurring among individuals (15).…”