Mitochondrial Disease-Specific Induced Pluripotent Stem Cell Models: Generation and Characterization

Zhang, Xuan; Li, Shishi; Yang, Wei; Pan, Huaye; Qin, Dajiang; Zhu, Xuemei; Yan, Qingfeng

doi:10.1007/7651_2014_195

Cited by 3 publications

(3 citation statements)

References 23 publications

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“…The generation of patient-specific iPSCs from urine samples was performed ( Zhou et al., 2012 , Zhang et al., 2016 ). Characterization of iPSCs was performed as reported previously, including alkaline phosphatase staining, expression of endogenous pluripotent genes, silencing of exogenous transgenes, transgene integration, immunocytochemistry, karyotyping, DNA methylation, and in vitro and in vivo differentiation.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Pan

Tan

et al. 2018

Stem Cell Reports

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SummaryHypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young individuals. A potential role of mtDNA mutations in HCM is known. However, the underlying molecular mechanisms linking mtDNA mutations to HCM remain poorly understood due to lack of cell and animal models. Here, we generated induced pluripotent stem cell-derived cardiomyocytes (HCM-iPSC-CMs) from human patients in a maternally inherited HCM family who carry the m.2336T>C mutation in the mitochondrial 16S rRNA gene (MT-RNR2). The results showed that the m.2336T>C mutation resulted in mitochondrial dysfunctions and ultrastructure defects by decreasing the stability of 16S rRNA, which led to reduced levels of mitochondrial proteins. The ATP/ADP ratio and mitochondrial membrane potential were also reduced, thereby elevating the intracellular Ca2+ concentration, which was associated with numerous HCM-specific electrophysiological abnormalities. Our findings therefore provide an innovative insight into the pathogenesis of maternally inherited HCM.

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Section: Methodsmentioning

confidence: 99%

Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Pan

Tan

et al. 2018

Stem Cell Reports

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“…In the cardiovascular system, urine cell-derived functional cardiomyocytes were shown to generate action potentials, both in vitro and in vivo, following differentiation of reprogrammed iPSCs by lentiviral-vector gene transduction [42]. With respect to metabolic diseases, iPSCs were generated from urine cells from one patient with a mitochondrial DNA mutation [43]. In the endocrine system, human urine-derived stem cells facilitated diabetic wound repair by promoting angiogenesis [44].…”

Section: (4) Reprogrammed Stem Cells Since 2006 Whenmentioning

confidence: 99%

Advances in Pluripotent Stem Cells: History, Mechanisms, Technologies, and Applications

Liu

David

Trawczynski

et al. 2019

Stem Cell Rev and Rep

348

209

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Over the past 20 years, and particularly in the last decade, significant developmental milestones have driven basic, translational, and clinical advances in the field of stem cell and regenerative medicine. In this article, we provide a systemic overview of the major recent discoveries in this exciting and rapidly developing field. We begin by discussing experimental advances in the generation and differentiation of pluripotent stem cells (PSCs), next moving to the maintenance of stem cells in different culture types, and finishing with a discussion of three-dimensional (3D) cell technology and future stem cell applications. Specifically, we highlight the following crucial domains: 1) sources of pluripotent cells; 2) next-generation in vivo direct reprogramming technology; 3) cell types derived from PSCs and the influence of genetic memory; 4) induction of pluripotency with genomic modifications; 5) construction of vectors with reprogramming factor combinations; 6) enhancing pluripotency with small molecules and genetic signaling pathways; 7) induction of cell reprogramming by RNA signaling; 8) induction and enhancement of pluripotency with chemicals; 9) maintenance of pluripotency and genomic stability in induced pluripotent stem cells (iPSCs); 10) feeder-free and xenon-free culture environments; 11) biomaterial applications in stem cell biology; 12) three-dimensional (3D) cell technology; 13) 3D bioprinting; 14) downstream stem cell applications; and 15) current ethical issues in stem cell and regenerative medicine. This review, encompassing the fundamental concepts of regenerative medicine, is intended to provide a comprehensive portrait of important progress in stem cell research and development. Innovative technologies and real-world applications are emphasized for readers interested in the exciting, promising, and challenging field of stem cells and those seeking guidance in planning future research direction.

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“…The appearance of iPSCs in 2006 (Takahashi and Yamanaka, 2006) has led to numerous possibilities in the field of disease modeling. In fact, it has been a great step forward in the study of neurodegenerative diseases (Ebert et al, 2009;Lee et al, 2009;Kondo et al, 2013), as well as mitochondrial diseases (Cherry et al, 2013;Kodaira et al, 2015;Chou et al, 2016;Zhang et al, 2016;Inak et al, 2017;Lorenz et al, 2017;Yang et al, 2018). These iPSCs can be differentiated into somatic cell types such as neurons, which allow the study of these diseases in one of the most affected cellular types.…”

Section: Cellular Modelsmentioning

confidence: 99%

Advances in mt-tRNA Mutation-Caused Mitochondrial Disease Modeling: Patients’ Brain in a Dish

et al. 2021

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Mitochondrial diseases are a heterogeneous group of rare genetic disorders that can be caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with several maternally inherited genetic diseases, with mitochondrial dysfunction as a main pathological feature. These diseases, although frequently multisystemic, mainly affect organs that require large amounts of energy such as the brain and the skeletal muscle. In contrast to the difficulty of obtaining neuronal and muscle cell models, the development of induced pluripotent stem cells (iPSCs) has shed light on the study of mitochondrial diseases. However, it is still a challenge to obtain an appropriate cellular model in order to find new therapeutic options for people suffering from these diseases. In this review, we deepen the knowledge in the current models for the most studied mt-tRNA mutation-caused mitochondrial diseases, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers) syndromes, and their therapeutic management. In particular, we will discuss the development of a novel model for mitochondrial disease research that consists of induced neurons (iNs) generated by direct reprogramming of fibroblasts derived from patients suffering from MERRF syndrome. We hypothesize that iNs will be helpful for mitochondrial disease modeling, since they could mimic patient’s neuron pathophysiology and give us the opportunity to correct the alterations in one of the most affected cellular types in these disorders.

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Mitochondrial Disease-Specific Induced Pluripotent Stem Cell Models: Generation and Characterization

Cited by 3 publications

References 23 publications

Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Advances in Pluripotent Stem Cells: History, Mechanisms, Technologies, and Applications

Advances in mt-tRNA Mutation-Caused Mitochondrial Disease Modeling: Patients’ Brain in a Dish

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