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Dysfunctional pancreatic cells differentiated from induced pluripotent stem cells with mitochondrial DNA mutations
Seongjun So1,2 (Graduate student), Song Lee3 (Research worker), Yeonmi Lee2 (Research worker), Jongsuk Han2 (Graduate student), Soonsuk Kang2 (Research worker), Jiwan Choi2 (Research worker), Bitnara Kim2 (Graduate student), Deokhoon Kim4 (Professor), Hyun-Ju Yoo1 (Professor), In-Kyong Shim1 (Professor), Ju-Yun Oh1 (Graduate student), Yu-Na Lee1 (Graduate student), Song-Cheol Kim1,3,# (Professor), Eunju Kang 1,*,# (Professor)
1Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine,
2Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Researc, CHA Advanced Research Institute, CHA University,
3Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery and 4Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine
Abstract
Diabetes mellitus (DM) is a serious disease in which blood sugar levels rise abnormally because of failed insulin production or decreased insulin sensitivity. Although many studies are being conducted for the treatment or early diagnosis of DM, it is not fully understood how mitochondrial genome (mtDNA) abnormalities appear in patients with DM. Here, we induced iPSCs from fibroblasts, PBMCs, or pancreatic cells of three patients with type 2 DM (T2D) and three patients with non-diabetes counterpart. The mtDNA mutations were detected randomly without any tendency among tissues or patients. In T2D patients, 62% (21/34) of iPSC clones harbored multiple mtDNA mutations, of which 37% were homoplasmy at the 100% mutation level compared to only 8% in non-diabetes. We next selected iPSC clones that were a wild type or carried mutations and differentiated into pancreatic cells. Oxygen consumption rates were significantly lower in cells carrying mutant mtDNA. Additionally, the mutant cells exhibited decreased production of insulin and reduced secretion of insulin in response to glucose. Overall, the results suggest that screening mtDNA mutations in iPSCs from patients with T2D is an essential step before pancreatic cell differentiation for disease modeling or autologous cell therapy.
Abstract, Accepted Manuscript(in press) [Submitted on February 10, 2022, Accepted on May 4, 2022]
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