Abstract
The human induced pluripotent stem cell (iPSC) technique promises to provide an unlimited, reliable source of genetically matched pluripotent cells for personalized therapy and disease modeling. Recently, it is observed that cells with ring chromosomes 13 or 17 autonomously correct the defects via compensatory uniparental disomy during cellular reprogramming to iPSCs. This breakthrough finding suggests a potential therapeutic approach to repair large-scale chromosomal aberrations. However, due to the scarceness of ring chromosome samples, the reproducibility of this approach in different individuals is not carefully evaluated yet. Moreover, the underlying mechanism and the applicability to other types of chromosomal aberrations remain unknown. Here we generated iPSCs from four 45,X chorionic villous fibroblast lines and found that only one reprogrammed line acquired 46,XX karyotype via uniparental disomy of the entire X chromosome. The karyotype correction was reproducible in the same cell line by either retroviral or episomal reprogramming. The karyotype-corrected iPSCs were subject to X chromosome inactivation and obtained better colony morphology and higher proliferation rate than other uncorrected ones. Further transcriptomic comparison among the fibroblast lines identified a distinct expression pattern of cell cycle regulators in the uncorrectable ones. These findings demonstrate that the iPSC technique holds the potential to correct X monosomy, but the correction rate is very low, probably due to differential regulation of cell cycle genes between individuals. Our data strongly suggest that more systematic investigations are needed before defining the iPSC technique as a novel means of chromosome therapy.
Highlights
Previous studies have demonstrated that cells with supernumerary or reduced number of chromosomes or other chromosomal aberrations can be reprogrammed into induced pluripotent stem cells by introducing four reprogramming factors [1,2,3]
Previous studies did not report growth defects in Turner syndrome (TS) induced pluripotent stem cells (iPSCs); most of their TS cell lines were derived from survived children, representing merely o1% TS patients that can survive to birth
Our TS cell lines were all derived from prenatal chorionic villous (CV) fibroblasts; we considered the varied growth phenotypes in our TS iPSC lines reflected the different degrees of embryo growth arrest observed in aborted TS fetuses [17]
Summary
Previous studies have demonstrated that cells with supernumerary or reduced number of chromosomes or other chromosomal aberrations can be reprogrammed into induced pluripotent stem cells (iPSCs) by introducing four reprogramming factors [1,2,3]. These iPSCs with aneuploidy syndromes have served as excellent disease models to deepen our understandings of these. Recent studies using human embryonic stem cell (hESC) models has identified haploinsufficiency of the XCI-escaping genes CSF2RA and ZFX as main reasons for early embryonic lethality and embryo growth defects of TS [15, 16] (Figure 1a). Owing to the profound and severe effects of whole chromosome loss that simultaneously affects numerous genes, no feasible therapy approach has been proposed yet
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