Type I interferon response impairs differentiation potential of pluripotent stem cells
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Upon virus infection, pluripotent stem cells neither induce nor respond to canonical type I interferons (IFN-I). To better understand this biology, we characterized induced pluripotent stem cells (iPSCs) as well as their differentiated parental or rederived counterparts. We confirmed that only iPSCs failed to respond to viral RNA, IFN-I, or viral infection. This lack of response could be phenocopied in fibroblasts with the expression of a reprogramming factor which repressed the capacity to induce canonical antiviral pathways. To ascertain the consequences of restoring the antiviral response in the context of pluripotency, we engineered a system to engage these defenses in iPSCs. Inducible expression of a recombinant virus-activated transcription factor resulted in the successful reconstitution of antiviral defenses through the direct up-regulation of IFN-I–stimulated genes. Induction of the antiviral signature in iPSCs, even for a short duration, resulted in the dysregulation of genes associated with all three germ layers despite maintaining pluripotency markers. Trilineage differentiation of these same cells showed that engagement of the antiviral defenses compromised ectoderm and endoderm formation and dysregulated the development of mesodermal sublineages. In all, these data suggest that the temporal induction of the antiviral response primes iPSCs away from pluripotency and induces numerous aberrant gene products upon differentiation. Together these results suggest that the IFN-I system and pluripotency may be incompatible with each other and thus explain why stem cells do not utilize the canonical antiviral system.Keywords:
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Induced pluripotent stem cells (iPSCs) were reprogrammed from somatic cells using specific transcription factors. Bypassing the ethical issue caused by embryonic stem cells (ESCs), iPSCs can be successfully induced from a variety of cells, which makes iPSCs a powerful research tool for developmental biology. iPSCs have also become indispensable to the research of life science due to their broad potential applications. However, it's a big challenge to obtain iPSCs with high quality and genetic stability. Here, we review the research progress of increasing the reprogramming mechanism and genetic stability of iPSCs in order to provide references of reprogramming efficiency of iPSCs, reducing the cost, and addressing key points of iPSCs quality control, further promoting clinical application of the iPSCs.
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Fibroblasts were isolated from skin biopsies of four patients diagnosed with schizophrenia and from one healthy control. Patient fibroblasts were transfected with five episomal, non-integrative reprogramming vectors to generate human induced pluripotent stem cells (iPSC). Reprogrammed iPSC showed consistent expression of several pluripotency markers, loss of expression of exogenous reprogramming vectors and ability to differentiate into all three germ layers. Additionally, iPSC maintained their normal karyotype during reprogramming. These generated cell lines can be used to study early neurodevelopmental and neuroinflammatory processes in schizophrenia in a patient-derived in vitro model.
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Induced pluripotent stem cells (iPSCs) technology is a method for generating pluripotent stem cells in vitro from fully differentiated cells such as fibroblast cells. The potential applications of iPSC technology in cell therapy and disease modeling could influence current medical practices. Despite current advances in iPSC technology, many patient-derived reprogrammed cells are not suitable for clinical trial because most protocols rely on virus-based techniques, which pose the risk of integration of the viral genome into the chromosomes. Therefore, non-viral methods such as mRNA and protein-based reprogramming are promising alternatives when generating clinically safe iPSCs. In a previous study, we generated human iPSCs using cell extracts with cell penetration peptide (CPP) for the delivery of reprogramming proteins [Kim et al. Cell Stem Cells, 2009]. In here, we show that the expression of reprogramming factors in mammalian cells and subsequent purification of these factors by FLAG-Tag could reprogram fibroblasts into iPSCs.
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Current advances in cellular reprogramming technology has demonstrated that the identity of a cell can be converted by the use of master transcription factors to reprogram the transcriptome.Notably, this allows us to convert somatic cells into induced pluripotent stem cells (iPSCs), providing a feasible method to generate patient-specific pluripotent stem cells.This technology was firstly discovered by Shinya Yamanaka's group in 2006.The initial iPSCs were formed by the induction of dedifferentiation in mouse fibroblasts using transcription factors: Oct4, Sox2, Klf4 and c-Myc.This approach has tremendous medical potentials to revolutionize the way we study and develop treatment for ocular diseases.Here we reviewed the potential of using patient-specific iPSCs for 3D disease modeling and various types of retinal disease modeling, cell replacement therapy and clinical trials, high-throughput screening test and drug toxicity testing.We also discussed the recent development of direct reprogramming and the future direction for utilising iPSCs and cellular reprogramming technology for eye research.
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Induced pluripotent stem cells; Cellular reprogramming; Retina; Disease modeling; Cell therapy; Drug screening
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Induced pluripotent stem cells can differentiate into a variety of cell types, which promote the development of human disease model, drug toxicity screening and sources of autologous cells.However, there have been many problems in the induced pluripotent stem cells reprogramming, such as safety and low efficiency.Small molecules are considered as a promising method to improve the reprogramming processes of induced pluripotent stem cell, and more and more small molecules have been identified to maintain stem cell self-renewal, providing a new approach to produce the desired reprogramming cells.
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Induced pluripotent stem cell; Small molecule; Reprogramming
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Induced pluripotent stem cells (iPSCs) are pluripotent cells derived from adult somatic cells. After the pioneering work by Yamanaka, who first generated iPSCs by retroviral transduction of four reprogramming factors, several alternative methods to obtain iPSCs have been developed in order to increase the yield and safety of the process. However, the question remains open on whether the different reprogramming methods can influence the pluripotency features of the derived lines. In this study, three different strategies, based on retroviral vectors, episomal vectors, and Sendai virus vectors, were applied to derive iPSCs from human fibroblasts. The reprogramming efficiency of the methods based on episomal and Sendai virus vectors was higher than that of the retroviral vector-based approach. All human iPSC clones derived with the different methods showed the typical features of pluripotent stem cells, including the expression of alkaline phosphatase and stemness maker genes, and could give rise to the three germ layer derivatives upon embryoid bodies assay. Microarray analysis confirmed the presence of typical stem cell gene expression profiles in all iPSC clones and did not identify any significant difference among reprogramming methods. In conclusion, the use of different reprogramming methods is equivalent and does not affect gene expression profile of the derived human iPSCs.
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The combination of OCT4 expression and short-term exposure to reprogramming media induces a state of transcriptional plasticity in human fibroblasts, capable of responding to changes in the extracellular environment. Here we provide characterization of iPSCs established through continued culture of OCT4-induced plastic human fibroblasts in pluripotent-supportive reprogramming media. Human iPSC(OCT4) are morphologically indistinguishable from conventionally derived iPSCs and express core proteins involved in maintenance of pluripotency. iPSC(OCT4) display bona fide functional pluripotency as measured by in vivo teratoma formation consisting of the three germ layers.
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Induced pluripotent stem cells (iPSCs) are a useful tool to investigate pathomechanistic and cellular processes due to their differentiation potential into different somatic cell types in vitro. Here, we have generated iPSCs from an apparently healthy male individual using an integration-free reprogramming method. The resulting iPSCs are pluripotent and display a normal karyotype. Furthermore, we demonstrate that this iPSC line can be differentiated into all three germ layers.
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