Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells
Journal of Clinical Investigation (Impact Factor: 13.22). 02/2012;
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
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- "iPSCs are laden with their own unique problems, namely chromosomal aberrations due to reprogramming, epigenetic differences due to variances in origins and integration of reprogramming factors which are naturally found in a lot of cancer cell types and contribute in conjunction with other genes to genomic instability (Ben-David and Benvenisty 2011). PSCs have also been observed to be exposed to the possibility of chromosomal instability during the course of differentiation (Varela et al. 2012). PSC-CMs are known to be immature, beat spontaneously (Rajala et al. 2011) and give rise to a mixture of cells with different action potential phenotypes which might lead to development of arrhythmias after engraftment (Zhang et al. 2002). "
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ABSTRACT: Many neurodegenerative disorders such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and others often occur as a result of progressive loss of structure or function of neurons. Recently, many groups were able to generate neural cells, either differentiated from induced pluripotent stem cells (iPSCs) or converted from somatic cells. Advances in converted neural cells have opened a new era to ease applications for modeling diseases and screening drugs. In addition, the converted neural cells also hold the promise for cell replacement therapy (Kikuchi et al., 2011; Krencik et al., 2011; Kriks et al., 2011; Nori et al., 2011; Rhee et al., 2011; Schwartz et al., 2012). Here we will mainly discuss most recent progress on using converted functional neural cells to treat neurological diseases and highlight potential clinical challenges and future perspectives.Protein & Cell 03/2012; 3(2):91-7. DOI:10.1007/s13238-012-2029-2 · 3.25 Impact Factor
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ABSTRACT: Adult stem cells have an enormous potential for clinical use in regenerative medicine that avoids many of the drawbacks characteristic of embryonic stem cells and induced pluripotent stem cells. In this context, easily obtainable human adipose-derived stem cells offer an interesting option for future strategies in regenerative medicine. However, little is known about their repertoire of differentiation capacities, how closely they resemble the target primary tissues, and the potential safety issues associated with their use. DNA methylation is one of the most widely recognized epigenetic factors involved in cellular identity, prompting us to consider how the analyses of 27,578 CpG sites in the genome of these cells under different conditions reflect their different natural history. We show that human adipose-derived stem cells generate myogenic and osteogenic lineages that share much of the DNA methylation landscape characteristic of primary myocytes and osteocytes. Most important, adult stem cells and in vitro-generated myocytes and osteocytes display a significantly different DNA methylome from that observed in transformed cells from these tissue types, such as rhabdomyosarcoma and osteosarcoma. These results suggest that the plasticity of the DNA methylation patterns plays an important role in lineage commitment of adult stem cells and that it could be used for clinical purposes as a biomarker of efficient and safely differentiated cells.American Journal Of Pathology 09/2012; 7(6). DOI:10.1016/j.ajpath.2012.08.016 · 4.59 Impact Factor
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