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  Mitochondrial-associated cell death mechanisms are reset to an embryonic-like state in aged donor-derived iPS cells harboring chromosomal aberrations

Prigione, A., Hossini, A. M., Lichtner, B., Serin, A., Fauler, B., Megges, M., et al. (2011). Mitochondrial-associated cell death mechanisms are reset to an embryonic-like state in aged donor-derived iPS cells harboring chromosomal aberrations. PLoS ONE, 6(11), e27352. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22110631 http://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0027352&representation=PDF.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-78CA-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-78CB-8
Genre: Journal Article

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Prigione, A.1, Author              
Hossini, A. M., Author
Lichtner, B.1, Author              
Serin, A.2, Author              
Fauler, B.3, Author              
Megges, M., Author
Lurz, R.3, Author              
Lehrach, H.4, Author              
Makrantonaki, E., Author
Zouboulis, C. C., Author
Adjaye, J.1, Author              
Affiliations:
1Molecular Embryology and Aging (James Adjaye), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479654              
2Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
3Imaging/Electron Microscopy (Head: Rudi Lurz/Thorsten Mielke), Scientific Service (Head: Manuela B. Urban), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
4Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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 Abstract: Somatic cells reprogrammed into induced pluripotent stem cells (iPSCs) acquire features of human embryonic stem cells (hESCs) and thus represent a promising source for cellular therapy of debilitating diseases, such as age-related disorders. However, reprogrammed cell lines have been found to harbor various genomic alterations. In addition, we recently discovered that the mitochondrial DNA of human fibroblasts also undergoes random mutational events upon reprogramming. Aged somatic cells might possess high susceptibility to nuclear and mitochondrial genome instability. Hence, concerns over the oncogenic potential of reprogrammed cells due to the lack of genomic integrity may hinder the applicability of iPSC-based therapies for age-associated conditions. Here, we investigated whether aged reprogrammed cells harboring chromosomal abnormalities show resistance to apoptotic cell death or mitochondrial-associated oxidative stress, both hallmarks of cancer transformation. Four iPSC lines were generated from dermal fibroblasts derived from an 84-year-old woman, representing the oldest human donor so far reprogrammed to pluripotency. Despite the presence of karyotype aberrations, all aged-iPSCs were able to differentiate into neurons, re-establish telomerase activity, and reconfigure mitochondrial ultra-structure and functionality to a hESC-like state. Importantly, aged-iPSCs exhibited high sensitivity to drug-induced apoptosis and low levels of oxidative stress and DNA damage, in a similar fashion as iPSCs derived from young donors and hESCs. Thus, the occurrence of chromosomal abnormalities within aged reprogrammed cells might not be sufficient to over-ride the cellular surveillance machinery and induce malignant transformation through the alteration of mitochondrial-associated cell death. Taken together, we unveiled that cellular reprogramming is capable of reversing aging-related features in somatic cells from a very old subject, despite the presence of genomic alterations. Nevertheless, we believe it will be essential to develop reprogramming protocols capable of safeguarding the integrity of the genome of aged somatic cells, before employing iPSC-based therapy for age-associated disorders.

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 Dates: 2011
 Publication Status: Published in print
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Title: PLoS ONE
Source Genre: Journal
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Pages: - Volume / Issue: 6 (11) Sequence Number: - Start / End Page: e27352 Identifier: ISSN: 1932-6203 (Electronic) 1932-6203 (Linking)