Document Detail


Mitochondrial-associated cell death mechanisms are reset to an embryonic-like state in aged donor-derived iPS cells harboring chromosomal aberrations.
MedLine Citation:
PMID:  22110631     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Alessandro Prigione; Amir M Hossini; Björn Lichtner; Akdes Serin; Beatrix Fauler; Matthias Megges; Rudi Lurz; Hans Lehrach; Eugenia Makrantonaki; Christos C Zouboulis; James Adjaye
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-11-14
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-11-23     Completed Date:  2012-03-26     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e27352     Citation Subset:  IM    
Affiliation:
Molecular Embryology and Aging Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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MeSH Terms
Descriptor/Qualifier:
Aged, 80 and over
Aging / genetics*,  pathology
Cell Death / genetics*
Chromosome Aberrations*
Female
Fibroblasts / cytology
Genomic Instability / genetics
Humans
Induced Pluripotent Stem Cells / cytology*,  metabolism*,  pathology
Karyotype
Mitochondria / metabolism*,  pathology
Nuclear Reprogramming
Oxidative Stress / genetics
Signal Transduction / genetics
Tissue Donors*
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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