The spontaneous differentiation and chromosome loss in iPSCs of human trisomy 18 syndrome

Ting Li,Lingling Zhang,Xu Han,Hanzhi Zhao,Ying Jin,Jiaying Yao,Dongmei Lai,Zhen Shao,Ying Guo

doi:10.1038/cddis.2017.565

Abstract

Aneuploidy including trisomy results in developmental disabilities and is the leading cause of miscarriages in humans. Unlike trisomy 21, pathogenic mechanisms of trisomy 18 remain unclear. Here, we successfully generated induced pluripotent stem cells (iPSCs) from human amniotic fluid cells (AFCs) with trisomy 18 pregnancies. We found that trisomy 18 iPSCs (18T-iPSCs) were prone to differentiate spontaneously. Intriguingly, 18T-iPSCs lost their extra 18 chromosomes and converted to diploid cells after 10 generations. fluorescence in situ hybridization analysis showed chromosome loss was a random event that might happen in any trisomic cells. Selection undifferentiated cells for passage accelerated the recovery of euploid cells. Overall, our findings indicate the genomic instability of trisomy 18 iPSCs bearing an extra chromosome 18.

Highlights

IntroductionTrisomy 18 ( known as Edward’s syndrome), caused by total or partial trisomy of chromosome 18, is a type of aneuploidy.[1]
Trisomy 18, caused by total or partial trisomy of chromosome 18, is a type of aneuploidy.[1]
We suggest that 18T-induced pluripotent stem cells (iPSC) have a spontaneous differentiation potential and a growth disadvantage that leads to the loss of extra chromosomes

Summary

Introduction

Trisomy 18 ( known as Edward’s syndrome), caused by total or partial trisomy of chromosome 18, is a type of aneuploidy.[1]. The APP gene, which locates on chromosome 21 and encodes β-amyloid precursor protein, is overexpressed in Down syndrome individuals and contributes to the early onset Alzheimer’s disease characteristic of this disease.[4,10] Changes in the copy number of large regions of the genome can cause general non-gene-specific effects.[11] For example, all four cell lines of trisomies 1, 13, 16, or 19 show impaired proliferation ability and altered metabolic properties.[9] In addition, aneuploidy yeast strains share a few phenotypes, including defects in proliferation, increased glucose uptake, and increased sensitivity to proteotoxic stress, independent of the identity of the extra chromosomes.[12] Aneuploidy drives genomic instability in yeast, which may facilitate the development of genetic alterations that drive tumorigenesis in cancers.[13]. We suggest that 18T-iPSCs have a spontaneous differentiation potential and a growth disadvantage that leads to the loss of extra chromosomes

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