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Stem Cell Reports. 2019 Dec 10;13(6):1126-1141. doi: 10.1016/j.stemcr.2019.11.003.

Precision Health Resource of Control iPSC Lines for Versatile Multilineage Differentiation.

Author information

1
Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
2
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
3
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
4
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
5
Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
6
Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
7
Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, ON M5C 2T2, Canada; The Joint Centre for Bioethics, University of Toronto, Toronto, ON, Canada; Unity Health Toronto, Toronto, ON M5T 3M6, Canada.
8
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
9
Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
10
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
11
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada. Electronic address: stephen.scherer@sickkids.ca.
12
Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jellis@sickkids.ca.

Abstract

Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings.

KEYWORDS:

Personal Genome Project Canada; cellular phenotyping; control iPSCs; disease modeling; gene editing; whole-genome sequencing

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