Stem cells and modeling of autism spectrum disorders

Freitas, Beatriz C.G.; Trujillo, Cleber A.; Carromeu, Cassiano; Yusupova, Marianna; Herai, Roberto H.; Muotri, Alysson R.

doi:10.1016/j.expneurol.2012.09.017

Cited by 26 publications

(19 citation statements)

References 150 publications

(175 reference statements)

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“…Since the development of iPSCs (Takahashi et al 2007), fibroblasts have been largely used in modeling diseases (Freitas et al 2012;Martinez-Santamaria et al 2012;Marchetto et al 2010;Dimos et al 2008;Park et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, fibroblasts derived from skin are frequently used to produce induced pluripotent stem cells, or iPSCs (Takahashi et al 2007), a powerful tool that allows production of other kinds of desired cells, which is now being widely used for disease modeling in vitro (Freitas et al 2012;Ring et al 2012;Chang et al 2011;Marchetto et al 2010;Dimos et al, 2008;Park et al 2008). The use of iPSC technique for disease modeling is particularly important because it makes possible to generate the cell target of the disease by still keeping the genetic background from the patient, which is extremely important-no matter if the disease is monogenetic, with an identified mutation or if the genetic cause remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Fibroblast sources: Where can we get them?

et al. 2014

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Fibroblasts are cells widely used in cell culture, both for transient primary cell culture or permanent as transformed cell lines. Lately, fibroblasts become cell sources for use in disease modeling after cell reprogramming because it is easily accessible in the body. Fibroblasts in patients will maintain all genetic background during reprogramming into induced pluripotent stem cells. In spite of their large use, fibroblasts are obtained after an invasive procedure, a superficial punch skin biopsy, collected under patient's local anesthesia. Taking into consideration the minimum patient's discomfort during and after the biopsy procedure, as well as the aesthetics aspect, it is essential to reflect on the best site of the body for the biopsy procedure combined with the success of getting robust fibroblast cultures in the lab. For this purpose, we compared the efficiency of four biopsy sites of the body (skin from eyelid, back of the ear, abdominal cesarean scar and groin). Cell proliferation assays and viability after cryopreservation were measured. Our results revealed that scar tissue provided fibroblasts with higher proliferative rates. Also, fibroblasts from scar tissues presented a higher viability after the thawing process.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fibroblast sources: Where can we get them?

et al. 2014

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“…Reprogramming of somatic cells to a pluripotent state by over-expression of specific genes has been accomplished using human cells 18, 19 . Induced pluripotent stem cells (iPSCs) are attractive models for understanding complex diseases and disorders with heritable and sporadic conditions 20 . Although iPSCs have been generated for monogenetic ASD diseases 4, 21, 22 , the demonstration of disease-specific pathogenesis in complex and heterogeneous disease such as sporadic ASD is a current challenge in the field 23 .…”

Section: Introductionmentioning

confidence: 99%

Altered proliferation and networks in neural cells derived from idiopathic autistic individuals

et al. 2016

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Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology, and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation due to dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by IGF-1, a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.

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“…In addition to overcoming ethical issues, this new technique has gained attention for its potential to generate disease-specific pluripotent stem cells with unprecedented simplicity. Human iPSCs are tempting models for understanding complex disorders with heritable and sporadic conditions, which allow researchers to recapitulate an individual’s development in the laboratory(50). …”

Section: A Human Pluripotent Experimental Model For Asdmentioning

confidence: 99%

The Human Model: Changing Focus on Autism Research

Muotri

2016

Biological Psychiatry

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The lack of live human brain cells for research has slowed progress toward understanding the mechanisms underlying autism spectrum disorders (ASDs). A human model using reprogrammed patient somatic cells offers an attractive alternative as it captures a patient’s genome in relevant cell types. Despite the current limitations, the disease-in-a-dish approach allows for progressive time-course analyses of target cells, offering a unique opportunity to investigate the cellular and molecular alterations before symptomatic onset. Understanding the current drawbacks of this model is essential for the correct data interpretation and extrapolation of conclusions applicable to the human brain. Innovative strategies for collecting biological material and clinical information from large patient cohorts are important for increasing the statistical power that will allow for the extraction of information from the noise resulting from the variability introduced by reprogramming and differentiation methods. Working with large patient cohorts is also important for understanding how brain cells derived from diverse human genetic backgrounds respond to specific drugs, creating the possibility of personalized medicine for ASD.

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Stem cells and modeling of autism spectrum disorders

Cited by 26 publications

References 150 publications

Fibroblast sources: Where can we get them?

Fibroblast sources: Where can we get them?

Altered proliferation and networks in neural cells derived from idiopathic autistic individuals

The Human Model: Changing Focus on Autism Research

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