Limits...
Progress and bottleneck in induced pluripotency.

Zhang ZN, Xu Y - Cell Regen (Lond) (2012)

Bottom Line: Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency.To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification.Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla California 92093-0322 USA.

ABSTRACT
With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of individual patients with defined factors, have unlimited potential in cell therapy and in modeling complex human diseases. Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency. To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification. In addition, a panel of small molecule compounds, many of which targeting the epigenetic machinery, have been identified to increase the reprogramming efficiency. Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs. In addition, due to the oncogenic potential of the reprogramming factors and the reprogramming-induced DNA damage, the critical tumor suppressor pathways such as p53 and ARF are activated to act as the checkpoints that suppress induced pluripotency. The inactivation of these tumor suppression pathways even transiently during reprogramming processes could have significant adverse impact on the genome integrity. These safety concerns must be resolved to improve the feasibility of the clinic development of iPSCs into human cell therapy.

No MeSH data available.


Related in: MedlinePlus

Genetic and epigenetic abnormalities in iPSCs. Induced pluripotency leads to genetic and epigenetic defects in iPSCs including genomic DNA mutation, abnormal genomic DNA methylation and gene expression, copy number variation and chromosomal aneuploidy.
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Fig1: Genetic and epigenetic abnormalities in iPSCs. Induced pluripotency leads to genetic and epigenetic defects in iPSCs including genomic DNA mutation, abnormal genomic DNA methylation and gene expression, copy number variation and chromosomal aneuploidy.

Mentions: When considering the clinic application of iPSC and ESCs, iPSCs appear to have several advantages over ESCs. For example, the generation of iPSCs avoids using human embryos, a major ethic concern for the generation of hESCs. The cells derived from patient-specific iPSCs are considered autologous cells and thus will not be rejected by the patient’s immune system. In addition, iPSCs derived from human patients offer the first opportunity to model human diseases with complex traits. Recent studies, however, have raised the concern of the safety of iPSCs in clinic application. While the global gene expression profile of iPSCs is very close to ESCs, there remains transcriptional signature that can distinguish between iPSCs and ESCs (Figure 1) [94]. Recent studies have also identified significant epigenetic differences between iPSCs and ESCs. By comparing genetically identical ESCs and iPSCs, it has been shown that expression levels for two genes (Gtl2 and Rian) and 21 miRNAs, all present on the imprinted Dlk1-Dio3 gene cluster on Chromosome 12qF1, differ significantly. Because of the developmental role of the Dlk1-Dio3 gene cluster, these iPSCs contributed poorly to chimaeras and failed to develop into adult animals with tetraploid complementation [95, 96]. In addition, iPSCs appear to retain some DNA methylation signatures of their somatic cells of origin, called epigenetic memory [97, 98]. The epigenetic memory could potentiate the gene expression during the iPSCs differentiation that favors the differentiation to the original lineage, while restricting the differentiation potential to other lineages [98]. In addition, by whole-genome profile of DNA methylation at the single-base resolution, recent studies have shown that iPSCs harbor both epigenetic memory and aberrant DNA methylation [99].Figure 1


Progress and bottleneck in induced pluripotency.

Zhang ZN, Xu Y - Cell Regen (Lond) (2012)

Genetic and epigenetic abnormalities in iPSCs. Induced pluripotency leads to genetic and epigenetic defects in iPSCs including genomic DNA mutation, abnormal genomic DNA methylation and gene expression, copy number variation and chromosomal aneuploidy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230504&req=5

Fig1: Genetic and epigenetic abnormalities in iPSCs. Induced pluripotency leads to genetic and epigenetic defects in iPSCs including genomic DNA mutation, abnormal genomic DNA methylation and gene expression, copy number variation and chromosomal aneuploidy.
Mentions: When considering the clinic application of iPSC and ESCs, iPSCs appear to have several advantages over ESCs. For example, the generation of iPSCs avoids using human embryos, a major ethic concern for the generation of hESCs. The cells derived from patient-specific iPSCs are considered autologous cells and thus will not be rejected by the patient’s immune system. In addition, iPSCs derived from human patients offer the first opportunity to model human diseases with complex traits. Recent studies, however, have raised the concern of the safety of iPSCs in clinic application. While the global gene expression profile of iPSCs is very close to ESCs, there remains transcriptional signature that can distinguish between iPSCs and ESCs (Figure 1) [94]. Recent studies have also identified significant epigenetic differences between iPSCs and ESCs. By comparing genetically identical ESCs and iPSCs, it has been shown that expression levels for two genes (Gtl2 and Rian) and 21 miRNAs, all present on the imprinted Dlk1-Dio3 gene cluster on Chromosome 12qF1, differ significantly. Because of the developmental role of the Dlk1-Dio3 gene cluster, these iPSCs contributed poorly to chimaeras and failed to develop into adult animals with tetraploid complementation [95, 96]. In addition, iPSCs appear to retain some DNA methylation signatures of their somatic cells of origin, called epigenetic memory [97, 98]. The epigenetic memory could potentiate the gene expression during the iPSCs differentiation that favors the differentiation to the original lineage, while restricting the differentiation potential to other lineages [98]. In addition, by whole-genome profile of DNA methylation at the single-base resolution, recent studies have shown that iPSCs harbor both epigenetic memory and aberrant DNA methylation [99].Figure 1

Bottom Line: Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency.To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification.Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla California 92093-0322 USA.

ABSTRACT
With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of individual patients with defined factors, have unlimited potential in cell therapy and in modeling complex human diseases. Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency. To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification. In addition, a panel of small molecule compounds, many of which targeting the epigenetic machinery, have been identified to increase the reprogramming efficiency. Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs. In addition, due to the oncogenic potential of the reprogramming factors and the reprogramming-induced DNA damage, the critical tumor suppressor pathways such as p53 and ARF are activated to act as the checkpoints that suppress induced pluripotency. The inactivation of these tumor suppression pathways even transiently during reprogramming processes could have significant adverse impact on the genome integrity. These safety concerns must be resolved to improve the feasibility of the clinic development of iPSCs into human cell therapy.

No MeSH data available.


Related in: MedlinePlus