Generation of two human iPSC lines, FINCBi002-A and FINCBi003-A, carrying heteroplasmic macrodeletion of mitochondrial DNA causing Pearson’s syndrome

Peron, Camille; Mauceri, Roberta; Iannielli, Angelo; Cavaliere, Andrea; Legati, Andrea; Rizzo, Ambra; Sciacca, Francesca L.; Broccoli, Vania; Tiranti, Valeria

doi:10.1016/j.scr.2020.102151

Cited by 5 publications

(5 citation statements)

References 6 publications

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“…In this sense, the nuclear genetic background of the recipient ρ 0 cell could influence the segregation of mutant and wild-type mtDNA in cybrids with mitochondrial mutations (Dunbar et al, 1995). iPSC bearing a mtDNA deletion, the most wanted model in recent years since it allows the study of specific affected tissue, have been described only in a few cases (Cherry et al, 2013;Russell et al, 2018;Peron et al, 2021). iPSC conserved the patient´s genetic background and they have the advantage of being euploid cells, but these are difficult to generate.…”

Section: Discussionmentioning

confidence: 99%

“…iPSCs bearing an mtDNA deletion, the most wanted model in recent years as it allows the study of specific affected tissue, have been described in only a few cases ( Cherry et al, 2013 ; Russell et al, 2018 ; Peron et al, 2021 ). iPSCs conserved the patient's genetic background and they have the advantage of being euploid cells.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding cell models, cybrids, generated by fusing platelets or enucleated fibroblasts with a cell line devoid of mtDNA (ρ° cells), have been the most used model ( Hayashi et al, 1991 ; Porteous et al, 1998 ; Van Den Ouweland et al, 2000 ). Although some studies on fibroblasts and induced pluripotent stem cells (iPSCs) bearing mtDNA deletions have also been reported ( Bourgeron et al, 1993 ; Van De Corput et al, 1997 ; Van Den Ouweland et al, 2000 ; Cherry et al, 2013 ; Russell et al, 2018 ; Peron et al, 2021 ), comparative analysis among different cell types with different deletions have not been previously described. In addition, studies in cell types that allow differentiation into specific tissues affected in Pearson syndrome patients are scarce.…”

Section: Introductionmentioning

confidence: 99%

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Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome

Hernández-Ainsa

López‐Gallardo

García-Jiménez

et al. 2022

Disease Models &Amp; Mechanisms

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Pearson syndrome (PS) is a rare multisystem disease caused by single large scale mitochondrial DNA deletions (SLSMDs). PS presents early in infancy and it is mainly characterized by refractory sideroblastic anaemia. Prognosis is poor and treatment is supportive, thus development of new models for the study of PS and new therapy strategies is essential. In this work we report three different cell models carrying a SLMSD: fibroblasts, transmitochondrial cybrids and induced pluripotent stem cells (iPSC). All studied models exhibited an aberrant mitochondrial ultrastructure and defective OXPHOS function, showing a decrease in different parameters such as mitochondrial ATP, respiratory complex IV activity and quantity or oxygen consumption. Despite that, iPSC harbouring “common deletion” were able to differentiate into three germ layers. Besides, cybrids clones only showed mitochondrial dysfunction when heteroplasmy level reached 70%. Some differences observed among models may depend on their metabolic profile, therefore we consider these three models are useful for the in vitro study of the PS as well as for testing new specific therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome

Hernández-Ainsa

López‐Gallardo

García-Jiménez

et al. 2022

Disease Models &Amp; Mechanisms

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“…Human iPSCs carrying large‐scale mtDNA deletions have been generated from patients affected by KSS and PMPS (Cherry et al , 2013 ; Russell et al , 2018 ; Lester Sequiera et al , 2021 ; Peron et al , 2021 ; Hernández‐Ainsa et al , 2022 ). Initial studies showed defects in hematopoietic progenitors (Cherry et al , 2013 ), but the contribution of mtDNA deletions to the disease pathogenesis in differentiated progenies has not been addressed in detail.…”

Section: Ipscs and 3d Organoids As Next‐g...mentioning

confidence: 99%

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem‐cell‐derived organoids

2023

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Mitochondrial DNA (mtDNA) diseases are multi-systemic disorders caused by mutations affecting a fraction or the entirety of mtDNA copies. Currently, there are no approved therapies for the majority of mtDNA diseases. Challenges associated with engineering mtDNA have in fact hindered the study of mtDNA defects. Despite these difficulties, it has been possible to develop valuable cellular and animal models of mtDNA diseases. Here, we describe recent advances in base editing of mtDNA and the generation of three-dimensional organoids from patient-derived human-induced pluripotent stem cells (iPSCs). Together with already available modeling tools, the combination of these novel technologies could allow determining the impact of specific mtDNA mutations in distinct human cell types and might help uncover how mtDNA mutation load segregates during tissue organization. iPSC-derived organoids could also represent a platform for the identification of treatment strategies and for probing the in vitro effectiveness of mtDNA gene therapies. These studies have the potential to increase our mechanistic understanding of mtDNA diseases and may open the way to highly needed and personalized therapeutic interventions.

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“…As shown in Table 1 and Figure 1A , the number of clones obtained was in general very low, even if numerous attempts were performed also in different laboratories. Conversely, using fibroblasts derived from healthy controls or disease's patients affected by mitochondrial disorders, including dominant optic atrophy ( OPA1 mutation), Pearson ( 40 ), and MPAN ( 41 ), we obtained on average from 10 to 20 clones of hiPSC ( Table 1 and Figure 1B ) per reprogramming experiment. To overcome this issue, we tested the reprogramming efficiency of LHON cells under hypoxia laboratory conditions (5% pO 2 , more similar to physiological oxygen tension in vivo ), a condition previously used to enhance the generation of hiPSC ( 42 ), and recently demonstrated to be specifically beneficial in several OXPHOS defects, by improving disease phenotype in mice and cells ( 43 ).…”

Section: Reprogramming Fibroblasts or Peripheral Blood Mononuclear Cells Pbmcs From Lhon Patientsmentioning

confidence: 99%

Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

et al. 2021

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More than 30 years after discovering Leber's hereditary optic neuropathy (LHON) as the first maternally inherited disease associated with homoplasmic mtDNA mutations, we still struggle to achieve effective therapies. LHON is characterized by selective degeneration of retinal ganglion cells (RGCs) and is the most frequent mitochondrial disease, which leads young people to blindness, in particular males. Despite that causative mutations are present in all tissues, only a specific cell type is affected. Our deep understanding of the pathogenic mechanisms in LHON is hampered by the lack of appropriate models since investigations have been traditionally performed in non-neuronal cells. Effective in-vitro models of LHON are now emerging, casting promise to speed our understanding of pathophysiology and test therapeutic strategies to accelerate translation into clinic. We here review the potentials of these new models and their impact on the future of LHON patients.

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Generation of two human iPSC lines, FINCBi002-A and FINCBi003-A, carrying heteroplasmic macrodeletion of mitochondrial DNA causing Pearson’s syndrome

Cited by 5 publications

References 6 publications

Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome

Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem‐cell‐derived organoids

Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

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