Natural underlying mtDNA heteroplasmy as a potential source of intra‐person hiPSC variability |
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| Authors: | Ester Perales‐Clemente Alexandra N Cook Jared M Evans Samantha Roellinger Frank Secreto Valentina Emmanuele Devin Oglesbee Vamsi K Mootha Michio Hirano Eric A Schon Andre Terzic Timothy J Nelson |
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| Institution: | 1. Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Division of Cardiovascular Diseases, Mayo Clinic Center for Regenerative Medicine, Rochester, MN, USA;2. Departments of Cardiovascular Diseases, Molecular Pharmacology and Experimental Therapeutics, Division of General Internal Medicine, Division of Pediatric Cardiology, and Transplant Center, Mayo Clinic Center for Regenerative Medicine, Rochester, MN, USA;3. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;5. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy;6. Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA, USA;7. Department of Neurology, Columbia University Medical Center, New York, NY, USA;8. Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA |
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| Abstract: | Functional variability among human clones of induced pluripotent stem cells (hiPSCs) remains a limitation in assembling high‐quality biorepositories. Beyond inter‐person variability, the root cause of intra‐person variability remains unknown. Mitochondria guide the required transition from oxidative to glycolytic metabolism in nuclear reprogramming. Moreover, mitochondria have their own genome (mitochondrial DNA mtDNA]). Herein, we performed mtDNA next‐generation sequencing (NGS) on 84 hiPSC clones derived from a cohort of 19 individuals, including mitochondrial and non‐mitochondrial patients. The analysis of mtDNA variants showed that low levels of potentially pathogenic mutations in the original fibroblasts are revealed through nuclear reprogramming, generating mutant hiPSCs with a detrimental effect in their differentiated progeny. Specifically, hiPSC‐derived cardiomyocytes with expanded mtDNA mutations non‐related with any described human disease, showed impaired mitochondrial respiration, being a potential cause of intra‐person hiPSC variability. We propose mtDNA NGS as a new selection criterion to ensure hiPSC quality for drug discovery and regenerative medicine. |
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| Keywords: | global private mutation human iPSC intra‐person variability mitochondrial DNA quality control universal heteroplasmy |
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