Trisomy correction in Down syndrome induced pluripotent stem cells.
Human trisomies can alter cellular phenotypes and produce congenital abnormalities such as Down syndrome (DS). Here we have generated induced pluripotent stem cells (iPSCs) from DS fibroblasts and introduced a TKNEO transgene into one copy of chromosome 21 by gene targeting. When selecting against TKNEO, spontaneous chromosome loss was the most common cause for survival, with a frequency of ~10(-4), while point mutations, epigenetic silencing, and TKNEO deletions occurred at lower frequencies in this unbiased comparison of inactivating mutations. Mitotic recombination events resulting in extended loss of heterozygosity were not observed in DS iPSCs. The derived, disomic cells proliferated faster and produced more endothelia in vivo than their otherwise isogenic trisomic counterparts, but in vitro hematopoietic differentiation was not consistently altered. Our study describes a targeted removal of a human trisomy, which could prove useful in both clinical and research applications.
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Li B
LB
Li
Kai-Hsin
KH
Chang
Pei-Rong
PR
Wang
Roli K
RK
Hirata
Thalia
T
Papayannopoulou
David W
DW
Russell
D002454:Cell Differentiation; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000235:genetics*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D018390:Gene Targeting; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D014314:Trisomy