Production and characterization of human induced pluripotent stem cells (iPSC) CSSi007-A (4383) from Joubert Syndrome

Altieri, Filomena; D'Anzi, Angela; Martello, Francesco; Tardivo, Silvia; Spasari, Iolanda; Ferrari, Daniela; Bernardini, Laura; Lamorte, Giuseppe; Mazzoccoli, Gianluigi; Valente, Enza Maria; Vescovi, Angelo L.; Rosati, Jessica

doi:10.1016/j.scr.2019.101480

Cited by 3 publications

(3 citation statements)

References 3 publications

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“…In this light, iPSCs represent a simple and efficient model to study abnormal neuronal development in ciliopathies such as JS. To date, a few studies have reported the generation of iPSCs carrying mutations in JS-related genes, including AHI1 (Rosati et al 2018 ; Altieri et al 2019 ; Serpieri et al 2023 ), CPLANE1 (Ali et al 2020 ), CC2D2A (Ali et al 2021 ), CEP290 (Shimada et al 2017 ; May-Simera et al 2018 ), RPGRIP1L (Wang et al 2019 ), and TMEM67 (Barabino et al 2020 ); however, these studies did not systematically analyze differentiation markers or compare ciliary phenotypes. The present study employed iPSCs derived from patients carrying pathogenic variants in four of the five common genes causative of JS, which were differentiated towards mid-hindbrain precursors and cerebellar neurons in order to address two main research questions: (1) do JS-derived iPSCs show aberrant differentiation along the cerebellar lineage?…”

Section: Discussionmentioning

confidence: 99%

“…Barabino et al also reported abnormal ciliary phenotype in a TMEM67 -mutant iPSC line, although in this case more numerous, but shorter and thinner cilia were observed, suggesting that different mutations in the same JS gene can lead to different outcomes. Moreover, iPSCs from RPGRIP1L -mutated JS patients showed a reduction in the number of ciliated neurons formed upon differentiation (Altieri et al 2019 ), while JS iPSCs mutated in CEP290 , when differentiated towards retinal epithelium lineages, showed smaller cilia associated with incomplete lineage maturation (Rosati et al 2018 ). Further in vitro observations made in other ciliopathy models, such as another iPSC line from a CEP290 -mutated patient with Leber’s congenital amaurosis and differentiated towards retinal pigment epithelium, also showed alterations in primary cilium formation and incidence (Parfitt et al 2016 ).…”

Section: Discussionmentioning

confidence: 99%

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Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro

De Mori,

Tardivo,

Pollara

et al. 2024

Cell Tissue Res

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Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the “molar tooth sign.” Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper, we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67, and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro

De Mori,

Tardivo,

Pollara

et al. 2024

Cell Tissue Res

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“…Skin fibroblasts have typically been used as a cell source to produce iPSCs, while efforts have been made to derive iPSCs from more easily accessible cell types, such as human keratinocytes obtained from a hair pluck,61 peripheral blood cells62 and URECs 63. Reprogramming procedures with the Yamanaka’s factors1 2 have moved from the use of an integrating viral-based route (eg, lentiviruses or adeno-associated viruses (AAVs)), to non-integrating viral vectors or virus-free reprogramming kits, taking advantage of non-integrative episomal vectors, as those used to generate iPSCs from patients with JS 64 65…”

Section: Modelling Primary Ciliopathies: From Animal Models To Patien...mentioning

confidence: 99%

Patient-derived cellular models of primary ciliopathies

2022

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Primary ciliopathies are rare inherited disorders caused by structural or functional defects in the primary cilium, a subcellular organelle present on the surface of most cells. Primary ciliopathies show considerable clinical and genetic heterogeneity, with disruption of over 100 genes causing the variable involvement of several organs, including the central nervous system, kidneys, retina, skeleton and liver. Pathogenic variants in one and the same gene may associate with a wide range of ciliopathy phenotypes, supporting the hypothesis that the individual genetic background, with potential additional variants in other ciliary genes, may contribute to a mutational load eventually determining the phenotypic manifestations of each patient. Functional studies in animal models have uncovered some of the pathophysiological mechanisms linking ciliary gene mutations to the observed phenotypes; yet, the lack of reliable human cell models has previously limited preclinical research and the development of new therapeutic strategies for primary ciliopathies. Recent technical advances in the generation of patient-derived two-dimensional (2D) and three-dimensional (3D) cellular models give a new spur to this research, allowing the study of pathomechanisms while maintaining the complexity of the genetic background of each patient, and enabling the development of innovative treatments to target specific pathways. This review provides an overview of available models for primary ciliopathies, from existing in vivo models to more recent patient-derived 2D and 3D in vitro models. We highlight the advantages of each model in understanding the functional basis of primary ciliopathies and facilitating novel regenerative medicine, gene therapy and drug testing strategies for these disorders.

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A Concise Review on Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Personalized Regenerative Medicine

Pushp

Rodrigues

Ferreira

et al. 2020

Stem Cell Rev and Rep

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Production and characterization of human induced pluripotent stem cells (iPSC) CSSi007-A (4383) from Joubert Syndrome

Cited by 3 publications

References 3 publications

Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro

Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro

Patient-derived cellular models of primary ciliopathies

A Concise Review on Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Personalized Regenerative Medicine

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