Altered neuroepithelial morphogenesis and migration defects in iPSC-derived cerebral organoids and 2D neural stem cells in familial bipolar disorder

Author:

Phalnikar Kruttika1,Srividya M2,Mythri S V2,Vasavi N S2,Ganguly Archisha1ORCID,Kumar Aparajita1,S Padmaja1,Kalia Kishan1,Mishra Srishti S1,Dhanya Sreeja Kumari1,Paul Pradip2,Holla Bharath2,Ganesh Suhas2,Reddy Puli Chandramouli3,Sud Reeteka2,Viswanath Biju2,Muralidharan Bhavana1ORCID

Affiliation:

1. Institute for Stem Cell Science and Regenerative Medicine (inStem) , GKVK - Post, Bellary Road, Bengaluru, Karnataka, India-560065

2. National Institute of Mental Health and Neurosciences (NIMHANS) , Hosur Road Bengaluru, Karnataka, India-560029

3. Shiv Nadar Institution of Eminence Centre of Excellence in Epigenetics, Department of Life Sciences, , Delhi-NCR, India-201314

Abstract

Abstract Bipolar disorder (BD) is a severe mental illness that can result from neurodevelopmental aberrations, particularly in familial BD, which may include causative genetic variants. In the present study, we derived cortical organoids from BD patients and healthy (control) individuals from a clinically dense family in the Indian population. Our data reveal that the patient organoids show neurodevelopmental anomalies, including organisational, proliferation and migration defects. The BD organoids show a reduction in both the number of neuroepithelial buds/cortical rosettes and the ventricular zone size. Additionally, patient organoids show a lower number of SOX2-positive and EdU-positive cycling progenitors, suggesting a progenitor proliferation defect. Further, the patient neurons show abnormal positioning in the ventricular/intermediate zone of the neuroepithelial bud. Transcriptomic analysis of control and patient organoids supports our cellular topology data and reveals dysregulation of genes crucial for progenitor proliferation and neuronal migration. Lastly, time-lapse imaging of neural stem cells in 2D in vitro cultures reveals abnormal cellular migration in BD samples. Overall, our study pinpoints a cellular and molecular deficit in BD patient-derived organoids and neural stem cell cultures.

Funder

Centre for Brain and Mind

M.K. Bhan Young researcher postdoctoral fellowship

Department of Biotechnology and the Pratiksha Trust

DBT- Har Gobind Khorana Innovative Young Biotechnologist Fellowship

DST-SERB

DBT-inStem, DBT/Wellcome Trust India Alliance: Intermediate Career Fellowship

Scientific Knowledge for Ageing and Neurological Ailments (SKAN) trust

DBT/Wellcome Trust India Alliance: Intermediate Clinical Fellowship

DBT/Wellcome Trust India Alliance: Early Career Fellowship

Publisher

Oxford University Press (OUP)

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