Microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological diseases

Yiling Hong; Xu Dong; Lawrence Chang; Chen Xie; Mariann Chang; Jose S Aguilar; Jimmy Lin; Juncheng Lin; Qingshun Q Li

doi:10.1016/j.isci.2023.106267

Microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological diseases

iScience. 2023 Feb 24;26(3):106267. doi: 10.1016/j.isci.2023.106267. eCollection 2023 Mar 17.

Authors

Yiling Hong¹, Xu Dong², Lawrence Chang², Chen Xie¹, Mariann Chang¹, Jose S Aguilar¹, Jimmy Lin², Juncheng Lin², Qingshun Q Li^{2

3}

Affiliations

¹ College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
² Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
³ Biomedical Sciences, College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA.

Abstract

Microglia play an important role in neuroinflammation and neurodegeneration. Here, we report an approach for generating microglia-containing cerebral organoids derived from human pluripotent stem cells involving the supplementation of growth factors (FGF, EGF, heparin) and 10% CO2 culture conditions. Using this platform, Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) cerebral organoids were generated from patient-derived induced pluripotent stem cells (iPSCs). These ALS-PDC-affected organoids had more reactive astrocytes and M1 microglia, and had fewer M2 microglia than their unaffected counterparts, leading to impaired microglia-mediated phagocytosis. RNA-seq analysis of ALS-PDC and control organoids indicated that the most significant changes were microglia- and astrocyte-related genes (IFITM1/2, TGF-β, and GFAP). The most significantly downregulated pathway was type I interferon signaling. Interferon-gamma supplementation increased IFITM expression, enhanced microglia-mediated phagocytosis, and reduced beta-amyloid accumulation in ALS-PDC-affected network. The results demonstrated the feasibility of using microglia-containing organoids for the study of neurodegenerative diseases.

Keywords: Cell biology; Immunology; Neuroscience; Stem cells research.