Showing papers by "Eirini P. Papapetrou published in 2016"
TL;DR: The authors' formerly proposed GSH criteria are reviewed and additional considerations on extending these criteria are discussed, on strategies for the identification and validation of GSHs, as well as future prospects on GSH targeting for therapeutic applications.
166 citations
TL;DR: The main advantages and limitations of iPSC modeling are discussed, and how the method intersects with other patient-derived models of cancer, such as organoids, organs-on-chips and patient- derived xenografts (PDXs).
Abstract: Together with recent advances in the processing and culture of human tissue, bioengineering, xenotransplantation and genome editing, Induced pluripotent stem cells (iPSCs) present a range of new opportunities for the study of human cancer. Here we discuss the main advantages and limitations of iPSC modeling, and how the method intersects with other patient-derived models of cancer, such as organoids, organs-on-chips and patient-derived xenografts (PDXs). We highlight the opportunities that iPSC models can provide beyond those offered by existing systems and animal models and present current challenges and crucial areas for future improvements toward wider adoption of this technology.
113 citations
TL;DR: iPSC technology has provided an invaluable tool for disease-oriented and translational researchers, bridging reductionism with patient-derived relevance and enabled investigation that was hitherto only possible in model organisms.
Abstract: Ten years ago, Shinya Yamanaka and his student Kazutoshi Takahashi did an experiment of exquisite simplicity and elegance that changed biomedical research forever ( 1 ). By showing that a set of transcription factors could reprogram somatic cells to acquire a pluripotent stem cell state, they ushered in the era of induced pluripotent stem cells (iPSCs). The discovery made it crystal clear that cell identity is much more malleable than previously thought, and provided an invaluable tool for disease-oriented and translational researchers, bridging reductionism with patient-derived relevance. Combined with other maturing technologies, most notably genome editing and three-dimensional (3D) cell culture systems, iPSC technology has enabled investigation that was hitherto only possible in model organisms ( 2 , 3 ).
29 citations
TL;DR: It is shown that induced pluripotent stem cells (iPSCs) expressing a let7-regulated HSVtk transgene are selectively killed by ganciclovir (GCV), whereas differentiated cells are fully protected, and in contrast to previous studies, it is found that in vivo GCV administration results in longer latency but does not prevent teratoma formation.
Abstract: Human pluripotent stem cells (hPSCs) hold great promise for cell therapy. However, a major concern is the risk of tumor formation by residual undifferentiated cells contaminating the hPSC-derived cell product. Suicide genes could safeguard against such adverse events by enabling elimination of cells gone astray, but the efficacy of this approach has not yet been thoroughly tested. Here, we engineered a lentivirally encoded herpes simplex virus thymidine kinase (HSVtk) with expression restricted to undifferentiated hPSCs through regulation by the let7 family of miRNAs. We show that induced pluripotent stem cells (iPSCs) expressing a let7-regulated HSVtk transgene are selectively killed by ganciclovir (GCV), whereas differentiated cells are fully protected. However, in contrast to previous studies, we find that in vivo GCV administration results in longer latency but does not prevent teratoma formation by iPSCs expressing either a constitutive or a let7-regulated HSVtk, without evidence of silencing of the HSVtk. Clonal analyses of iPSCs expressing HSVtk revealed frequent emergence of GCV resistance which, at least in some cases, could be attributed to preexisting inactivating mutations in the HSVtk coding sequence, selected for upon GCV treatment. Our findings have important consequences for the future use of suicide genes in hPSC-based cell therapies.
21 citations
TL;DR: It is found that the splicing inhibitor E7107, as well as small molecule inhibitors of kinases modulating splicing, preferentially inhibit the growth of SRSF2 mutant, but not of isogenic normal, iPSC-derived HPCs and undifferentiated iPSCs from mutant and isogenic wild-type (WT) i PSCs.
2 citations
TL;DR: Preliminary data suggest that SDS-iPSCs retain the capacity to give rise to hematopoietic stem/progenitor cells and early myeloid progenitor cells in vitro, which is of interest to understand the molecular mechanisms underlying leukemia predisposition and develop more effective treatments.
2 citations
TL;DR: A lentiviral screen in human induced pluripotent stem cells (iPSCs) is performed and it is demonstrated that different transgenes can be inserted therein rapidly and efficiently through recombinase-mediated cassette exchange (RMCE).
Abstract: Transgenesis of human pluripotent stem cells (hPSCs) can enable and empower a variety of studies in stem cell research, including lineage tracing and functional genetics studies. While in recent years much progress has been made in the development of tools for gene targeting, little attention has been given to the identification of sites in the human genome where transgenes can be inserted and reliably expressed. In order to find human genomic sites capable of supporting long-term and high-level transgene expression in hPSCs, we performed a lentiviral screen in human induced pluripotent stem cells (iPSCs). We isolated 40 iPSC clones each harboring a single vector copy and characterized the level of transgene expression afforded by each unique integration site. We selected one clone, LiPS-A3 with an integration site in chromosome 15 maintaining robust expression without silencing and demonstrate that different transgenes can be inserted therein rapidly and efficiently through recombinase-mediated cassette exchange (RMCE). The LiPS-A3 line can greatly facilitate the insertion of reporter and other genes in hPSCs. Targeting transgenes in the LiPS-A3S genomic locus can find broad applications in stem cell research and possibly cell and gene therapy.
1 citations