Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells

Abstract

Human pluripotent stem cells offer a limitless source of cells for regenerative medicine. Neural derivatives of human embryonic stem cells (hESCs) are currently being used for cell therapy in 3 clinical trials. However, hESCs are prone to genomic instability, which could limit their clinical utility. Here, we report that neural differentiation of hESCs systematically produced a neural stem cell population that could be propagated for more than 50 passages without entering senescence; this was true for all 6 hESC lines tested. The apparent spontaneous loss of evolution toward normal senescence of somatic cells was associated with a jumping translocation of chromosome 1q. This chromosomal defect has previously been associated with hematologic malignancies and pediatric brain tumors with poor clinical outcome. Neural stem cells carrying the 1q defect implanted into the brains of rats failed to integrate and expand, whereas normal cells engrafted. Our results call for additional quality controls to be implemented to ensure genomic integrity not only of undifferentiated pluripotent stem cells, but also of hESC derivatives that form cell therapy end products, particularly neural lines.

Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q

“…Trisomy of entire chromosome 1 has been reported in human pluripotent stem cells as well as gains of small region of chromosome 1. 12,34,37 A recent study reported about a recurrent chromosomal duplication of chromosome 1q in neural pluripotent stem cells, 42 but duplication of almost the entire 1q arm had not been observed in pluripotent stem cells. Duplication of the chromosome segment of 1q11-1q32 is associated with advantages in proliferation and metastasis formation 43 and data from several reports suggest that alterations in chromosome 1, and especially in the 1q region may have a significant role in disease evolution by providing a growth and/or survival advantage.…”

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

“…Even though the potential risk for tumor formation in these cells should be low, genetic changes can affect their performance and functional activities when replacing damaged tissues (76,93). An additional way to safeguard iPSCgenerated cells from overproliferation or teratoma formation after transplantation is to insert inducible suicide genes that can be regulated using prodrugs (94 -96).…”

Induced neural stem cells: a new tool for studying neural development and neurological disorders

“…3) Is the iNSC reprogramming process free of genomic alterations? In fact, it has been shown that NSCs derived from human embryonic stem cells have abnormal karyotypes with long-term culture in vitro [17]. In this regard, safety issues would need to be carefully evaluated in iNSCs and their derivatives before cell therapy applications can be considered.…”