Investigation of the role of Microglia derived from iPSC in Autism Spectrum Disorder.

Author(s)

Andrelissa Gorete Castanha

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-02-09

Examining board members

Patricia Cristina Baleeiro Beltrao Braga; Alexandre Bruni Cardoso; Paulo Emílio Corrêa Leite; Marilene Hohmuth Lopes

• Advisor: Patricia Cristina Baleeiro Beltrao Braga

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with high functional impairment, where patients present behavioral changes such as repetitive and stereotyped movements, communication deficit, and socialization problems. The worldwide prevalence of ASD is very high, being around 1-2% of the world population. The diagnosis of patients with ASD usually occurs at the age of three, being more common in boys. Studying the biology of TEA is a challenge due to the lack of access to cells in the nervous system of patients. In 2007, a new technique capable of reprogramming somatic cells, generating pluripotent stem cells (in English called Induced Pluripotent Stem Cells, iPSC) was described. Our group has been carrying out the modeling of idiopathic TEA in vitro through iPSC, with subsequent cell differentiation in Central Nervous System (CNS) cells. Our results revealed that iPSC-derived neurons from patients with ASD had alterations in synaptogenesis and connectivity. Furthermore, co-culture experiments with iPSC-derived neurons and astrocytes independently revealed that astrocytes from control subjects were able to rescue the morphology and synaptic capacity of neurons derived from patients with idiopathic ASD. Another finding was the neuroinflammatory profile of astrocytes from patients with ASD, with the exacerbated production of some cytokines such as IL6. Also considering the neuroinflammatory profile of patients with ASD observed in astrocytes, the purpose of this work was to produce microglia derived from iPSC and investigate the role of these cells in ASD. Microglia is a glial cell that plays a preponderant role in the immune control of the CNS, plays a role in synaptic plasticity and neurogenesis, and the maintenance of CNS homeostasis. Considering these functions of microglia, this work aimed to investigate the cellular and molecular phenotypes of microglia produced from iPSC of patients with idiopathic ASD, in particular, the profile of cytokine production. This project established the first protocol for the production of microglia derived from iPSC in Brazil. Our results are still preliminary, but we observed that hematopoietic progenitors, as well as microglial and differentiated microglia, showed similarities in morphology between control and autistic patients, as already observed between iPSCs and NPCs, requiring further investigation to verify the role of these cells in the TEA phenotype. (AU)

• FAPESP's process: 19/02784-5 - Investigation of the role of microglia derived from iPSC in Autism Spectrum Disorder
• Grantee: Andrelissa Gorete Castanha
• Support Opportunities: Scholarships in Brazil - Master