TY - JOUR
T1 - Age-related accumulation of somatic mitochondrial DNA mutations in adult-derived human ipscs
AU - Kang, Eunju
AU - Wang, Xinjian
AU - Tippner-Hedges, Rebecca
AU - Ma, Hong
AU - Folmes, Clifford D.L.
AU - Gutierrez, Nuria Marti
AU - Lee, Yeonmi
AU - Van Dyken, Crystal
AU - Ahmed, Riffat
AU - Li, Ying
AU - Koski, Amy
AU - Hayama, Tomonari
AU - Luo, Shiyu
AU - Harding, Cary O.
AU - Amato, Paula
AU - Jensen, Jeffrey
AU - Battaglia, David
AU - Lee, David
AU - Wu, Diana
AU - Terzic, Andre
AU - Wolf, Don P.
AU - Huang, Taosheng
AU - Mitalipov, Shoukhrat
N1 - Funding Information:
The authors acknowledge the OHSU Embryonic Stem Cell Research Oversight Committee and the Institutional Review Board for oversight and guidance. We thank all study participants for tissue donations and the Women’s Health Research Unit staff, University Fertility Consultants and the Reproductive Endocrinology and Infertility Division in the Department of Obstetrics and Gynecology, Oregon Health & Science University for support and procurement of human gametes. We are indebted to Dr. Masahito Tachibana, Michelle Sparman, and Ammar Husami for technical support. Studies were supported by the Leducq Foundation, OHSU institutional funds, and the Mayo Clinic Center for Regenerative Medicine. E.K. was partially funded by a fellowship from the Collins Medical Trust.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/5
Y1 - 2016/5/5
N2 - The genetic integrity of iPSCs is an important consideration for therapeutic application. In this study, we examine the accumulation of somatic mitochondrial genome (mtDNA) mutations in skin fibroblasts, blood, and iPSCs derived from young and elderly subjects (24-72 years). We found that pooled skin and blood mtDNA contained low heteroplasmic point mutations, but a panel of ten individual iPSC lines from each tissue or clonally expanded fibroblasts carried an elevated load of heteroplasmic or homoplasmic mutations, suggesting that somatic mutations randomly arise within individual cells but are not detectable in whole tissues. The frequency of mtDNA defects in iPSCs increased with age, and many mutations were non-synonymous or resided in RNA coding genes and thus can lead to respiratory defects. Our results highlight a need to monitor mtDNA mutations in iPSCs, especially those generated from older patients, and to examine the metabolic status of iPSCs destined for clinical applications.
AB - The genetic integrity of iPSCs is an important consideration for therapeutic application. In this study, we examine the accumulation of somatic mitochondrial genome (mtDNA) mutations in skin fibroblasts, blood, and iPSCs derived from young and elderly subjects (24-72 years). We found that pooled skin and blood mtDNA contained low heteroplasmic point mutations, but a panel of ten individual iPSC lines from each tissue or clonally expanded fibroblasts carried an elevated load of heteroplasmic or homoplasmic mutations, suggesting that somatic mutations randomly arise within individual cells but are not detectable in whole tissues. The frequency of mtDNA defects in iPSCs increased with age, and many mutations were non-synonymous or resided in RNA coding genes and thus can lead to respiratory defects. Our results highlight a need to monitor mtDNA mutations in iPSCs, especially those generated from older patients, and to examine the metabolic status of iPSCs destined for clinical applications.
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U2 - 10.1016/j.stem.2016.02.005
DO - 10.1016/j.stem.2016.02.005
M3 - Article
C2 - 27151456
AN - SCOPUS:84963550687
SN - 1934-5909
VL - 18
SP - 625
EP - 636
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 5
ER -