Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program

Kanika Kanchan; Kruthika Iyer; Lisa R Yanek; Ivan Carcamo-Orive; Margaret A Taub; Claire Malley; Kristin Baldwin; Lewis C Becker; Ulrich Broeckel; Linzhao Cheng; Chad Cowan; Matteo D'Antonio; Kelly A Frazer; Thomas Quertermous; Gustavo Mostoslavsky; George Murphy; Marlene Rabinovitch; Daniel J Rader; Martin H Steinberg; Eric Topol; Wenli Yang; Joshua W Knowles; Cashell E Jaquish; Ingo Ruczinski; Rasika A Mathias

Stem Cell Research (Jul 2020)

Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program

Kanika Kanchan,
Kruthika Iyer,
Lisa R Yanek,
Ivan Carcamo-Orive,
Margaret A Taub,
Claire Malley,
Kristin Baldwin,
Lewis C Becker,
Ulrich Broeckel,
Linzhao Cheng,
Chad Cowan,
Matteo D'Antonio,
Kelly A Frazer,
Thomas Quertermous,
Gustavo Mostoslavsky,
George Murphy,
Marlene Rabinovitch,
Daniel J Rader,
Martin H Steinberg,
Eric Topol,
Wenli Yang,
Joshua W Knowles,
Cashell E Jaquish,
Ingo Ruczinski,
Rasika A Mathias

Affiliations

Kanika Kanchan: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Kruthika Iyer: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Lisa R Yanek: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Ivan Carcamo-Orive: Department of Medicine, Cardiovascular Institute and Diabetes Research Center, Stanford University, School of Medicine, Stanford, CA, USA
Margaret A Taub: Department of Biostatistics, Bloomberg School of Public health, Johns Hopkins University, Baltimore, MD, USA
Claire Malley: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Kristin Baldwin: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA
Lewis C Becker: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Ulrich Broeckel: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
Linzhao Cheng: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Chad Cowan: Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
Matteo D'Antonio: Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
Kelly A Frazer: Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
Thomas Quertermous: Department of Medicine, Cardiovascular Institute and Diabetes Research Center, Stanford University, School of Medicine, Stanford, CA, USA
Gustavo Mostoslavsky: The Center for Regenerative Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
George Murphy: The Center for Regenerative Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
Marlene Rabinovitch: Department of Medicine, Cardiovascular Institute and Diabetes Research Center, Stanford University, School of Medicine, Stanford, CA, USA
Daniel J Rader: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Martin H Steinberg: Department of Medicine, Section of Hematology-Oncology, Boston University School of Medicine, Boston, MA, USA
Eric Topol: Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
Wenli Yang: Penn Center for Pulmonary Biology and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA
Joshua W Knowles: Department of Medicine, Cardiovascular Institute and Diabetes Research Center, Stanford University, School of Medicine, Stanford, CA, USA
Cashell E Jaquish: National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
Ingo Ruczinski: Department of Biostatistics, Bloomberg School of Public health, Johns Hopkins University, Baltimore, MD, USA
Rasika A Mathias: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Corresponding author.

Journal volume & issue: Vol. 46
p. 101803

Abstract

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Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined the structural integrity of 506 hiPSC lines as determined by copy number variations (CNVs). We observed that 149 hiPSC lines acquired 258 CNVs relative to donor DNA. We identified six recurrent regions of CNVs on chromosomes 1, 2, 3, 16 and 20 that overlapped with cancer associated genes. Furthermore, the genes mapping to regions of acquired CNVs show an enrichment in cancer related biological processes (IL6 production) and signaling cascades (JNK cascade & NFκB cascade). The genomic region of instability on chr20 (chr20q11.2) includes transcriptomic signatures for cancer associated genes such as ID1, BCL2L1, TPX2, PDRG1 and HCK. Of these HCK shows statistically significant differential expression between carrier and non-carrier hiPSC lines. Overall, while a low level of genomic instability was observed in the NextGen generated hiPSC lines, the observation of structural instability in regions with known cancer associated genes substantiates the importance of systematic evaluation of genetic variations in hiPSCs before using them as disease/research models.

Published in Stem Cell Research

ISSN: 1873-5061 (Print); 1876-7753 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: https://www.journals.elsevier.com/stem-cell-research

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