Effect of chromosome instability on the maintenance and differentiation of human embryonic stem cells in vitro and in vivo

Abstract

The therapeutic potential of human embryonic stem cells (hESCs) has long been appreciated, and the recent FDA approval of hESC derivatives for cell-based therapy encourages the clinical application of hESCs. Here, using CHA3-hESCs with normal and abnormal karyotypes, we report the importance of maintaining normal chromosomes during in vitro culture and the differentiation of hESCs for minimization of posttransplantation complications. We found that undifferentiated CHA3-hESCs with trisomy chromosome 12 undergo abnormal cell division with multiple spindles in comparison to the bipolar cell division of the karyotypically normal CHA3-hESCs. Transplanted karyotypically abnormal CHA3-hESC derivatives formed a tumor-like tissue 6weeks after transplantation in two out of seven mice tested. Our results demonstrate that the preservation of normal chromosomes is indispensable for maintaining the true properties of hESCs in vitro and abolishing adverse effects posttransplantation. Thus, the development of optimized techniques for stabilizing the chromosome state during in vitro hESC culture is a prerequisite for the therapeutic application of hESCs.

Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells

“…Although one study reported that teratomas from T12-hESCs are not significantly different in their gross composition 32 , another study reported that T12-hESCs undergo abnormal cell division 33 ; both studies, however, assessed only one cell line each, using limited experimental assays. In the current study, we compared the global gene expression signatures of dozens of hPSC and GCT cell lines, and revealed that trisomy 12 renders hPSCs more transcriptionally similar to GCTs.…”

Differentiation of hESCs into Mesodermal Subtypes: Vascular-, Hematopoietic- and Mesenchymal-lineage Cells

“…Recently, Moon et al demonstrated aberrant cell division in karyotypically abnormal hESCs during in vitro culture. These authors subsequently showed a post-transplant tumor-like tissue growth arising from the hESC transplant derivatives (68). These results emphasize that sustaining normal human chromosome number during in vitro culture and differentiation is indispensable for safe transplantation of hESC derivatives for therapeutic use.…”

Stem cell therapy for glaucoma: Science or snake oil?

“…91 Safety concerns common to both cells, such as teratoma formation, also require further investigation. 51,89 The ideal developmental stage for transplantation is also unclear. 56,120,122 In the field of photoreceptor regeneration, transplantation of post-mitotic rod precursors appears to result in superior differentiation and integration with the host retina.…”