title: Human embryonic stem cells as models for aneuploid chromosomal syndromes.
abstract: Syndromes caused by chromosomal aneuploidies are widely recognized genetic disorders in humans and often lead to spontaneous miscarriage. Preimplantation genetic screening is used to detect chromosomal aneuploidies in early embryos. Our aim was to derive aneuploid human embryonic stem cell (hESC) lines that may serve as models for human syndromes caused by aneuploidies. We have established 25 hESC lines from blastocysts diagnosed as aneuploid on day 3 of their in vitro development. The hESC lines exhibited morphology and expressed markers typical of hESCs. They demonstrated long-term proliferation capacity and pluripotent differentiation. Karyotype analysis revealed that two-third of the cell lines carry a normal euploid karyotype, while one-third remained aneuploid throughout the derivation, resulting in eight hESC lines carrying either trisomy 13 (Patau syndrome), 16, 17, 21 (Down syndrome), X (Triple X syndrome), or monosomy X (Turner syndrome). On the basis of the level of single nucleotide polymorphism heterozygosity in the aneuploid chromosomes, we determined whether the aneuploidy originated from meiotic or mitotic chromosomal nondisjunction. Gene expression profiles of the trisomic cell lines suggested that all three chromosomes are actively transcribed. Our analysis allowed us to determine which tissues are most affected by the presence of a third copy of either chromosome 13, 16, 17 or 21 and highlighted the effects of trisomies on embryonic development. The results presented here suggest that aneuploid embryos can serve as an alternative source for either normal euploid or aneuploid hESC lines, which represent an invaluable tool to study developmental aspects of chromosomal abnormalities in humans.
authors.affiliation: The International Stem Cell Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Biancotti
authors.forename: Kavita
authors.initials: K
authors.lastname: Narwani
authors.forename: Nicole
authors.initials: N
authors.lastname: Buehler
authors.forename: Berhan
authors.initials: B
authors.lastname: Mandefro
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan-Lev
authors.forename: Ofra
authors.initials: O
authors.lastname: Yanuka
authors.forename: Amander
authors.initials: A
authors.lastname: Clark
authors.forename: David
authors.initials: D
authors.lastname: Hill
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
authors.forename: Neta
authors.initials: N
authors.lastname: Lavon
mesh_terms: D000782:Aneuploidy; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D025063:Chromosome Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002877:Chromosomes, Human; D002882:Chromosomes, Human, Pair 13; D002885:Chromosomes, Human, Pair 16; D002886:Chromosomes, Human, Pair 17; D002891:Chromosomes, Human, Pair 21; D016000:Cluster Analysis; D053595:Embryonic Stem Cells / Q000473:pathology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005820:Genetic Testing; D006801:Humans; D007621:Karyotyping; D039904:Pluripotent Stem Cells / Q000473:pathology*; D019836:Preimplantation Diagnosis / Q000379:methods; D013577:Syndrome