Generation of Urine-Derived Induced Pluripotent Stem Cells and Cerebral Organoids for Modeling Down Syndrome

Author(s)

Teles e Silva, Andre Luiz ; Yokota, Bruno Yukio ; Sertie, Andrea Laurato ; Zampieri, Bruna Lancia

• Document type: Journal article
• Source: STEM CELL REVIEWS AND REPORTS; v. N/A, p. 8-pg., 2023-01-18.

Abstract

Down syndrome (DS, or trisomy 21, T21), is the most common genetic cause of intellectual disability. Alterations in the complex process of cerebral cortex development contribute to the neurological deficits in DS, although the underlying molecular and cellular mechanisms are not completely understood. Human cerebral organoids (COs) derived from three-dimensional (3D) cultures of induced pluripotent stem cells (iPSCs) provide a new avenue for gaining a better understanding of DS neuropathology. In this study, we aimed to generate iPSCs from individuals with DS (T21-iPSCs) and euploid controls using urine-derived cells, which can be easily and noninvasively obtained from most individuals, and examine their ability to differentiate into neurons and astrocytes grown in monolayer cultures, as well as into 3D COs. We employed nonintegrating episomal vectors to generate urine-derived iPSC lines, and a simple-to-use system to produce COs with forebrain identity. We observed that both T21 and control urine-derived iPSC lines successfully differentiate into neurons and astrocytes in monolayer, as well as into COs that recapitulate early features of human cortical development, including organization of neural progenitor zones, programmed differentiation of excitatory and inhibitory neurons, and upper-and deep-layer cortical neurons as well as astrocytes. Our findings demonstrate for the first time the suitability of using urine-derived iPSC lines to produce COs for modeling DS. (AU)

• FAPESP's process: 19/08655-2 - Functional analysis of rare genetic variants in Autism Spectrum Disorder: an oligonenic mode of inheritance?
• Grantee: Andréa Laurato Sertié
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/14491-2 - Investigation of the molecular and cellular mechanisms of oligogenic inheritance in Autism spectrum disorder
• Grantee: Andréa Laurato Sertié
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/04859-2 - Generation of induced pluripotent stem cells from epithelial cells in urine from individuals with Down Syndrome
• Grantee: Bruna Lancia Zampieri
• Support Opportunities: Scholarships in Brazil - Young Researchers
• FAPESP's process: 18/15371-8 - Generation of induced pluripotent stem cells from epithelial cells in urine from individuals with Down Syndrome
• Grantee: Bruna Lancia Zampieri
• Support Opportunities: Research Grants - Young Investigators Grants