Generation of induced pluripotent stem cells from patients with autism spectrum disorder

Author(s)

Fabiele Baldino Russo

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina Veterinária e Zootecnia (FMVZ/SBD)
• Defense date: 2015-03-27

Examining board members

Patricia Cristina Baleeiro Beltrao Braga; Helena Paula Brentani; Carlos Frederico Martins Menck; Graciela Conceição Pignatari; Rudimar dos Santos Riesgo

• Advisor: Patricia Cristina Baleeiro Beltrao Braga; Alysson Renato Muotri

Abstract

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by qualitative impairment communication, social interaction and restricted and repetitive patterns of behavior. The prevalence of 1 in every 50 children in The United States has been reported with a tendency to increase in recent years. Patient ASD diagnosis typically occurs by the age of 3 years and affects more boys than girls (4:1). The biological and genetic causes of autism has been studied in animal models, in human biological material such as blood and in post-mortem brain tissues. Although valuable, these models do not allow study of living human neural cells. The generation of functional neural cells from reprogrammed cells previously changed this scenario and opened doors to generate cellular models in vitro and to study diseases as autism. This study aimed to model ASD in vitro to study neurons and astrocytes derived from induced pluripotent stem cells from mesenchymal stem cells from dental pulp (SHED) from patients with idiopathic autism. In our results we found that neurons derived from patients with ASD show a significant decrease in synaptic genes compared with controls. Functional electrophysiology tests were performed and we were able to observe a smaller number of spike per second in neurons derived from patients, indicating that neurons from ASD patients has less activity than control neurons. In our co-culture assay between neurons and astrocytes we observed that astrocytes derived from patients may interfere in the maturation and morphological complexity of neurons derived from controls. On the other hand, when we grow ASD neurons on astrocytes from controls we can observe a significant increase in the level of synaptic markers, changes in morphology where we observe more mature and complex neurons. These data indicate that astrocytes influence in the maturity, complexity and functionality of neurons, data never shown before for ASD patients. With these results we can say that it is possible to model idiopathic autism in vitro. The iPSC technology and disease modeling opens doors to new discoveries and therapies for ASD patients (AU)

• FAPESP's process: 11/20683-0 - Generation of induced pluripotent cells of patients with autistic disorder
• Grantee: Fabiele Baldino Russo
• Support Opportunities: Scholarships in Brazil - Doctorate