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![Isogenic iPSCs from individual mosaic for trisomy 21 or from monozygotic twins discordant for trisomy 21. ( A ) Isogenic D21-iPSCs and T21-iPSCs have been derived from mosaic patients for trisomy 21 [19,20]; ( B ) Isogenic D21-iPSCs and T21-iPSCs have been generated from monozygotic twins discordant for trisomy 21 [22–24].](profile/Anis-Feki-2/publication/275254167/figure/fig2/AS:294542227066881@1447235747391/Isogenic-iPSCs-from-individual-mosaic-for-trisomy-21-or-from-monozygotic-twins-discordant.png)
Isogenic iPSCs from individual mosaic for trisomy 21 or from monozygotic twins discordant for trisomy 21. ( A ) Isogenic D21-iPSCs and T21-iPSCs have been derived from mosaic patients for trisomy 21 [19,20]; ( B ) Isogenic D21-iPSCs and T21-iPSCs have been generated from monozygotic twins discordant for trisomy 21 [22–24].
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Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Several models have been used to investigate th...
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Context 1
... leads to a combination of euploid cells and cells carrying trisomy 21 anomaly within individual tissues (reviewed in [74]). Taking advantage of this rare situation, two recent studies reported the derivation of isogenic D21-iPSCs and T21-iPSCs from fibroblasts from an individual mosaic for trisomy 21 ( Figure 2A) [19,20]. Isogenic D21-iPSCs and T21-iPSCs have been obtained either via spontaneous or induced loss of one copy of HSA21. ...
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... example of this is monozygotic twins discordant for trisomy 21 [76]. We exploited this rare and unique situation by deriving iPSCs from fetal fibroblasts of monozygotic twins discordant for trisomy 21 [22][23][24] and thus confounding effects from genomic variability were theoretically eliminated ( Figure 2B). [19,20]; (B) Isogenic D21-iPSCs and T21-iPSCs have been generated from monozygotic twins discordant for trisomy 21 [22][23][24]. ...
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Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this...
Citations
... microdeletion syndrome (MIM: 615656), 317 Prader-Willi syndrome (MIM: 608636), 318,319 and DS. [320][321][322][323][324] Some phenotypes in neural cells derived from these cells link to disease symptomology, whereas other phenotypes do not, and there is variability in the phenotypes in different reports. ...
... Down Syndrome. DS hESCs [337][338][339][340] and hiPSCs [320][321][322][323][324] have been established. The development of neurons has been primarily studied with iPSC-derived neurons, and these studies have revealed a common phenotype of oxidative stress and mitochondrial dysfunction that are consistent with many cell types from DS-affected individuals. ...
The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Human pluripotent stem cells have emerged as a much-needed model system for investigating human-specific biology and disease mechanisms. However, questions remain regarding whether these cell-culture-based models are sufficient or even necessary. In this review, we summarize human-specific features of neurodevelopment and the most common neurodevelopmental disorders, present discrepancies between animal models and human diseases, demonstrate how human stem cell models can provide meaningful information, and discuss the challenges that exist in our pursuit to understand distinctively human aspects of neurodevelopment and brain disease. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or animal, to mimic disease characteristics.
... In this respect, the discovery that human induced pluripotent stem cells (iPSCs) can be differentiated into neural cells has provided powerful in vitro models for disease modelling and drug screening [66]. Numerous studies have been successful in generating disease-specific iPSCs from patients with DS (reviewed in [67]). Among those, our study was the first pointing to a crucial role of DYRK1A in the neurodevelopmental defects of DS [40,68]. ...
... The discovery that human iPSCs can be differentiated into neural cells has allowed new opportunities for DS modelling, drug screening and perhaps for regenerative medicine purposes [66]. Over the past decade, several laboratories have succeeded in generating DS-iPSCs from patients with DS [67]. Brain-related defects are probably the most studied phenotype in iPSC-based models. ...
Down syndrome (DS) caused by a trisomy of chromosome 21 (HSA21), is the most common genetic developmental disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment, early onset of Alzheimer’s disease, congenital heart disease, hypotonia, muscle weakness and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Among the numerous protein coding genes of HSA21, dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) encodes a proline-directed serine/threonine and tyrosine kinase that plays pleiotropic roles in neurodevelopment in both physiological and pathological conditions. Numerous studies point to a crucial role of DYRK1A protein for brain defects in patients with DS. Thus, DYRK1A inhibition has shown benefits in several mouse models of DS, including improvement of cognitive behaviour. Lastly, a recent clinical trial has shown that epigallocatechine gallate (EGCG), a DYRK1A inhibitor, given to young patients with DS improved visual recognition memory, working memory performance and adaptive behaviour.
... Current achievements in cell reprogramming technology provide a unique method for overcoming this issue by the production of induced pluripotent stem (iPS) cells from the somatic cells of patients with chromosomal disorders. Several reports that demonstrate the value of this approach in modeling well-known chromosomal disorders such as Down syndrome [1,2] and Turner syndrome [3] have been published. Moreover, subsequent in vitro differentiation of iPS cells into neuronal cells makes it possible to directly assess transcriptional changes in targeted cells with chromosomal aneuploidy [4]. ...
Copy number variations (CNVs) of the human CNTN6 gene caused by megabase-scale microdeletions or microduplications in the 3p26.3 region are often the cause of neurodevelopmental disorders, including intellectual disability and developmental delay. Surprisingly, patients with different copy numbers of this gene display notable overlapping of neuropsychiatric symptoms. The complexity of the study of human neuropathologies is associated with the inaccessibility of brain material. This problem can be overcome through the use of reprogramming technologies that permit the generation of induced pluripotent stem (iPS) cells from fibroblasts and their subsequent in vitro differentiation into neurons. We obtained a set of iPS cell lines derived from a patient carrier of the CNTN6 gene duplication and from two healthy donors. All iPS cell lines displayed the characteristics of pluripotent cells. Some iPS cell lines derived from the patient and from healthy donors were differentiated in vitro by exogenous expression of the Ngn2 transcription factor or by spontaneous neural differentiation of iPS cells through the neural rosette stage. The obtained neurons showed the characteristics of mature neurons as judged by the presence of neuronal markers and by their electrophysiological characteristics. Analysis of allele-specific expression of the CNTN6 gene in these neuronal cells by droplet digital PCR demonstrated that the level of expression of the duplicated allele was significantly reduced compared to that of the wild-type allele. Importantly, according to the sequencing data, both copies of the CNTN6 gene, which were approximately 1 Mb in size, showed no any additional structural rearrangements.
... In recent years, several trisomy 21 iPSC (T21-iPSC) lines have been developed [9]. However, all but one of these studies used fibroblasts as starting cells, with the exception being a study that used cells harvested from amniotic fluid [10]. ...
... Another important issue to consider is the selection of a proper delivery method for the reprogramming factors. The T21-iPSC lines currently described in the literature have been primarily generated through integrative delivery systems [9,17]. Although this method is simple and efficient, the random integration of the vectors into host cell genomes can lead to insertion of mutagenesis in the obtained iPSCs [18]. ...
Down syndrome (DS) is a genetic disorder caused by trisomy 21 (T21). Over the past two decades, the use of mouse models has led to significant advances in the understanding of mechanisms underlying various phenotypic features and comorbidities secondary to T21 and even informed the design of clinical trials aimed at enhancing the cognitive abilities of persons with DS. In spite of its success, this approach has been plagued by all the typical limitations of rodent modeling of human disorders and diseases. Recently, several laboratories have succeeded in producing T21 human induced pluripotent stem cells (T21-iPSCs) from individuals with DS, which is emerging as a promising complementary tool for the study of DS. Here, we describe the method by which we generated 10 T21-iPSC lines from epithelial cells in urine samples, presumably from kidney epithelial origin, using nonintegrating episomal vectors. We also show that these iPSCs maintain chromosomal stability for well over 20 passages and are more sensitive to proteotoxic stress than euploid iPSCs. Furthermore, these iPSC lines can be differentiated into glutamatergic neurons and cardiomyocytes. By culturing urine-derived cells and maximizing the efficiency of episomal vector transfection, we have been able to generate iPSCs noninvasively and effectively from participants with DS in an ongoing clinical trial, and thus address most shortcomings of previously generated T21-iPSC lines. These techniques should extend the application of iPSCs in modeling DS and other neurodevelopmental and neurodegenerative disorders, and may lead to future human cell-based platforms for high-throughput drug screening. Stem Cells Translational Medicine 2017.
... La technologie iPSC a permis de traiter un patient atteint d'une maladie oculaire dégénérative. Cependant, leurs applications cliniques sont limitées en raison de leur immunogénicité et de leur tumorigénicité [Hibaoui et Feki, 2015]. Le programme "Scarcell", sélectionné par la Fondation Jérôme Lejeune, vise à démontrer l'efficacité de cellules souches issues de gencives dans le traitement des complications vasculaires, avec de possibles applications pour ses patients. ...
La trisomie 21 est définie par la présence d'un chromosome surnuméraire sur la 21ème paire, en totalité ou en partie, occasionnant des manifestations cliniques variables. Cette aneuploïdie peut résulter d’une translocation ou plus fréquemment d’une non-disjonction, le plus souvent d’origine méiotique maternelle, associée au facteur de risque de l’âge maternel, mais parfois aussi d’origine méiotique paternelle ou postzygotique mitotique. La surexpression des gènes tripliqués et leur interaction entre eux et avec d’autres gènes ont des répercussions multiples sur le phénotype. Certains gènes tripliqués dont DYRK1A, APP et RCAN1 ont un rôle prépondérant dans la maladie d’Alzheimer précoce. L’inactivation de certains de ces gènes représente un challenge thérapeutique. L’inhibition de produits géniques par des petites molécules telles que l’épigallocatéchine-3-gallate qui inhibe la kinase DYRK1A est également porteuse d’espoir. Diverses études cliniques ont permis d’estimer l’intérêt potentiel de différents médicaments et molécules innovantes pour les personnes porteuses de ce syndrome. À la condition qu’ils soient très spécifiques aux cibles pharmacologiques dont la perturbation est à corriger, et de ne pas augmenter la probabilité de survenue d’effets secondaires, ces traitements potentiels pourraient à long terme venir compléter les initiatives d’inclusion sociale et les méthodes de stimulation cognitive visant à faciliter la vie des personnes atteintes de trisomie 21.
... What would be the best donor cell type choice for reprogramming? The answer should be based on the use of iPS cells: disease modeling to study the basic mechanism of the disease, drug screening, or cell therapy [51] . Due to easy, well-validated cell culture procedures and high proliferation rate, fibroblasts are the most used cell type for the generation of iPS cells. ...
... Pluripotency is achieved more easily in young tissue (i.e. embryonic tissue) rather than adult tissue [51] . ...
Down Syndrome (DS), or Trisomy 21 Syndrome, is one of the most common genetic diseases. It is a chromosomal abnormality caused by a duplication of chromosome 21. DS patients show the presence of a third copy (or a partial third copy) of chromosome 21 (trisomy), as result of meiotic errors. These patients suffer of many health problems, such as intellectual disability, congenital heart disease, duodenal stenosis, Alzheimer's disease, leukemia, immune system deficiencies, muscle hypotonia and motor disorders. About one in 1000 babies born each year are affected by DS. Alterations in the dosage of genes located on chromosome 21 (also called HSA21) are responsible for the DS phenotype. However, the molecular pathogenic mechanisms of DS triggering are still not understood; newest evidences suggest the involvement of epigenetic mechanisms. For obvious ethical reasons, studies performed on DS patients, as well as on human trisomic tissues are limited. Some authors have proposed mouse models of this syndrome. However, not all the features of the syndrome are represented. Stem cells are considered the future of molecular and regenerative medicine. Several types of stem cells could provide a valid approach to offer a potential treatment for some untreatable human diseases. Stem cells also represent a valid system to develop new cell-based drugs and/or a model to study molecular disease pathways. Among stem cell types, patient-derived induced pluripotent stem (iPS) cells offer some advantages for cell and tissue replacement, engineering and studying: self-renewal capacity, pluripotency and ease of accessibility to donor tissues. These cells can be reprogrammed into completely different cellular types. They are derived from adult somatic cells via reprogramming with ectopic expression of four transcription factors (Oct3/4, Sox2, c-Myc and Klf4; or, Oct3/4, Sox2, Nanog, and Lin28). By reprogramming cells from DS patients, it is possible to obtain new tissue with the same genetic background, offering a valuable tool for studying this genetic disease and to design customized patient-specific stem cell therapies. © 2016, Journal of Stem Cells and Regenerative Medicine. All rights reserved.
Neurodevelopmental disorders are challenging to study in the laboratory, and despite a large investment, few novel treatments have been developed in the last decade. While animal models have been valuable in elucidating disease mechanisms and in providing insights into the function of specific genes, the predictive validity of preclinical models to test potential therapies has been questioned. In the last two decades, diverse new murine models of Down syndrome (DS) have been developed and numerous studies have demonstrated neurobiological alterations that could be responsible for the cognitive and behavioral phenotypes found in this syndrome. In many cases, similar alterations were found in murine models and in individuals with DS, although several phenotypes shown in animals have yet not been confirmed in the human condition. Some of the neurobiological alterations observed in mice have been proposed to account for their changes in cognition and behavior, and have received special attention because of being putative therapeutic targets. Those include increased oxidative stress, altered neurogenesis, overexpression of the Dyrk1A gene, GABA-mediated overinhibition and Alzheimer's disease-related neurodegeneration. Subsequently, different laboratories have tested the efficacy of pharmacotherapies targeting these alterations. Unfortunately, animal models are limited in their ability to mimic the extremely complex process of human neurodevelopment and neuropathology. Therefore, the safety and efficacy identified in animal studies are not always translated to humans, and most of the drugs tested have not demonstrated any positive effect or very limited efficacy in clinical trials. Despite their limitations, though, animal trials give us extremely valuable information for developing and testing drugs for human use that cannot be obtained from molecular or cellular experiments alone. This chapter reviews some of these therapeutic approaches and discusses some reasons that could account for the discrepancy between the findings in mouse models of DS and in humans, including: (i) the incomplete resemble of the genetic alterations of available mouse models of DS and human trisomy 21, (ii) the lack of evidence that some of the phenotypic alterations found in mice (e.g., GABA-mediated overinhibition, and alterations in adult neurogenesis) are also present in DS individuals, and (iii) the inaccuracy and/or inadequacy of the methods used in clinical trials to detect changes in the cognitive and behavioral functions of people with DS. Despite the shortcomings of animal models, animal experimentation remains an invaluable tool in developing drugs. Thus, we will also discuss how to increase predictive validity of mouse models.
