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Induced pluripotent stem cells generated from diabetic patients with mitochondrial DNA A3243G mutation
1Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. j-fuji@sannet.ne.jp
Diabetologia
|March 8, 2012
Summary
Induced pluripotent stem (iPS) cells were generated from patients with mitochondrial DNA (mtDNA) A3243G mutation. These mutation-specific iPS cells offer potential for disease modeling and autologous transplantation therapies.
Area of Science:
- Stem Cell Biology
- Mitochondrial Genetics
- Regenerative Medicine
Background:
- Mitochondrial DNA (mtDNA) mutations are linked to various human diseases.
- Generating patient-specific induced pluripotent stem (iPS) cells is crucial for disease modeling and therapeutic development.
- The A3243G mtDNA mutation is associated with conditions like MELAS syndrome.
Purpose of the Study:
- To generate patient-derived induced pluripotent stem (iPS) cells from individuals with the mitochondrial DNA (mtDNA) A3243G mutation.
- To characterize the stem cell properties and mtDNA mutation status of the generated iPS cells.
- To evaluate the potential of these cells for disease modeling and therapeutic applications.
Main Methods:
- Fibroblasts were obtained from skin biopsies of diabetic patients carrying the mtDNA A3243G mutation.
- Retroviral transduction with OCT4, SOX2, c-MYC, and KLF4 was used to reprogram fibroblasts into iPS cells.
- Stem cell characteristics were assessed, and mtDNA mutation frequencies were quantified using the Invader assay.
Main Results:
- Four and ten mitochondrial disease-specific iPS (Mt-iPS) clones were successfully generated from two patients.
- Mt-iPS clones exhibited normal cytogenetics, alkaline phosphatase activity, and expression of pluripotent markers.
- Epigenetic reprogramming was confirmed by unmethylated CpG islands in OCT4 and NANOG promoters.
- Mt-iPS cells demonstrated differentiation potential into all three germ layers in vitro and in vivo.
- A bimodal distribution of mtDNA mutation heteroplasmy was observed, with some clones showing undetectable mutation levels and others exhibiting increased frequencies (51-87%).
- No recurrence or significant changes in heteroplasmy levels were noted during serial culture and differentiation.
Conclusions:
- Successful generation of iPS cells from patients with the mtDNA A3243G mutation was achieved.
- Mutation-rich Mt-iPS cells are a promising resource for in vitro modeling of mitochondrial diseases.
- Mutation-free iPS cells hold potential for developing autologous cell transplantation therapies.
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