Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture

Louise C. Laurent, Igor Ulitsky, Ileana Slavin, Ha Tran, Andrew Schork, Robert Morey, Candace Lynch, Julie V. Harness, Sunray Lee, Maria J. Barrero, Sherman Ku, Marina Martynova, Ruslan Semechkin, Vasiliy Galat, Joel Gottesfeld, Juan Carlos Izpisua Belmonte, Chuck Murry, Hans S. Keirstead, Hyun Sook Park, Uli SchmidtAndrew L. Laslett, Franz Josef Muller, Caroline M. Nievergelt, Ron Shamir, Jeanne F. Loring

Research output: Contribution to journalArticlepeer-review

723 Scopus citations

Abstract

Genomic stability is critical for the clinical use of human embryonic and induced pluripotent stem cells. We performed high-resolution SNP (single-nucleotide polymorphism) analysis on 186 pluripotent and 119 nonpluripotent samples. We report a higher frequency of subchromosomal copy number variations in pluripotent samples compared to nonpluripotent samples, with variations enriched in specific genomic regions. The distribution of these variations differed between hESCs and hiPSCs, characterized by large numbers of duplications found in a few hESC samples and moderate numbers of deletions distributed across many hiPSC samples. For hiPSCs, the reprogramming process was associated with deletions of tumor-suppressor genes, whereas time in culture was associated with duplications of oncogenic genes. We also observed duplications that arose during a differentiation protocol. Our results illustrate the dynamic nature of genomic abnormalities in pluripotent stem cells and the need for frequent genomic monitoring to assure phenotypic stability and clinical safety.

Original languageEnglish (US)
Pages (from-to)106-118
Number of pages13
JournalCell Stem Cell
Volume8
Issue number1
DOIs
StatePublished - Jan 7 2011
Externally publishedYes

Bibliographical note

Funding Information:
We would like to acknowledge all of the collaborators who contributed samples to this study, including Eirini Papapetrou (Sadelain lab), Dongbao Chen, Ralph Graichen, Jerold Chun, Martin Pera, James Shen, Scott McKercher, Timo Otonkoski, and Sheng Ding. We would like to thank Gulsah Altun for invaluable assistance. We would like to thank the NICHD Brain and Tissue Bank for Developmental Disorders, Planned Parenthood of San Diego and Riverside Counties, and Christopher Barry for generously providing tissue specimens for this study. L.C.L. was supported by an NIH/NICHD K12 Career Development Award and the Hartwell Foundation. J.F.L., I.S., H.T., C.L., and F.-J.M. are supported by CIRM (CL1-00502, RT1-01108, TR1-01250, RN2-00931-1), NIH (R21MH087925), the Millipore Foundation, and the Esther O'Keefe Foundation. I.U. was supported in part by a fellowship from the Edmond J. Safra foundation in Tel Aviv University and by the Legacy stem cell research fund. I.S. was supported by the PEW Charitable Trust. H.-S.P. and S.L. were supported by a SCRC Grant (SC2250) of the 21st Century Frontier Research Program funded by the Ministry of Education, Science and Technology. M.J.B. was partially supported by grants RYC-2007-01510 and SAF2009-08588 from the Ministerio de Ciencia e Innovación of Spain. Work in the laboratory of J.C.I.B. was supported by grants from MICINN Fundacion Cellex, the G. Harold and Leila Y. Mathers Charitable Foundation, and Sanofi-Aventis. C.M. was supported by NIH grants R01 HL64387, P01 HL094374, R01 HL084642, and P01 GM081719. V.G. was partially supported by NHLBI, RC1HL100168. R. Shamir was supported in part by the Israel Science Foundation (grant no. 802/08). A.L.L. was supported by grants from the Australian Stem Cell Centre and from the Victoria-California Stem Cell Alliance (TR101250) between CIRM and the state government of Victoria, Australia. H.S.K. is the chairman of the scientific advisory board of California Stem Cell, Inc. R. Semechkin and M.M. are employees and shareholders of International Stem Cell Corporation.

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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