Cancer-like epigenetic derangements of human pluripotent stem cells and their impact on applications in regeneration and repair

Abstract

A growing body of work has raised concern that many human pluripotent stem cell (hPSC) lines possess tumorigenic potential following differentiation to clinically relevant lineages. In this review, we highlight recent work characterizing the spectrum of cancer-like epigenetic derangements in human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC) that are associated with reprogramming errors or prolonged culture that may contribute to such tumorigenicity. These aberrations include cancer-like promoter DNA hypermethylation and histone marks associated with pluripotency, as well as aberrant X-chromosome regulation. We also feature recent work that suggests optimized high-fidelity reprogramming derivation methods can minimize cancer-associated epigenetic aberrations in hPSC, and thus ultimately improve the ultimate clinical utility of hiPSC in regenerative medicine.

Stem cell based therapies for age-related macular degeneration: The promises and the challenges

“…Finally, there is growing concern about potential epigenetic remnants in both differentiated hESCs and iPSCs including cancerlike hypermethylation of promoter DNA, pluripotency-associated histone markers, and aberrant regulation of X-chromosomes (Huo et al, 2014). These genetic aberrations may increase the risk of dedifferentiation drift of the final therapeutic cell lineage (i.e., tumor formation).…”

“…These genetic aberrations may increase the risk of dedifferentiation drift of the final therapeutic cell lineage (i.e., tumor formation). Use of efficient, high-fidelity reprogramming derivation methods has been suggested to minimize cancerassociated epigenetic aberrations in iPSCs (Huo et al, 2014). Modifications of differentiation protocols (Tomoda et al, 2012) and in vitro detection of undifferentiated cells by flow cytometry assays using an anti-TRA-1-60 antibody and/or qRT-PCR to detect trace amounts of Lin28 mRNA have also been suggested to ensure detection of potential tumor-producing cells during the production of hESC-RPE and iPSC-RPE cells (Kuroda et al, 2012).…”

Nuclear Reprogramming by Defined Factors: Quantity Versus Quality

“…Genomic stability and epigenomic assembly are two of the most influential parameters that determine cell quality [33,79,80]. While complete nuclear resetting and an intact genome are essential in yielding functional and safe cells, an aberrant epigenomic landscape or genetic mutations might lead to unstable and dysfunctional cells that hold a high tumorigenic potential.…”

Effect of resveratrol on drug resistance in colon cancer chemotherapy

“…This may be related to the tumor stem cells, which are similar to the normal stem cells. Tumor stem cells possess a strong ability to regenerate, repair DNA, 5 and expel the chemotherapeutic drugs out of the cell. 6 Therefore, study of the resistance of stem cells to chemotherapeutic agents and how this resistance can be overcome is a topic of signicant interest in this eld.…”