Brain organoid models for studying the function of iPSC-derived microglia in neurodegeneration and brain tumours
Angélica María Sabogal-Guáqueta, Teresa Mitchell-Garcia, Jasmijn Hunneman, Daniëlle C. Voshart, Arun Thiruvalluvan, Floris Foijer, Frank A.E. Kruyt, Marina Trombetta-Lima, Bart J. L. Eggen, Erik Boddeke, Lara Barazzuol, Amalia M. Dolga
Abstract
Microglia represent the main resident immune cells of the brain. The interplay between microglia and other cells in the central nervous system, such as neurons or other glial cells, influences the function and ability of microglia to respond to various stimuli. These cellular communications, when disrupted, can affect the structure and function of the brain, and the initiation and progression of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, as well as the progression of other brain diseases like glioblastoma. Due to the difficult access to patient brain tissue and the differences reported in the murine models, the available models to study the role of microglia in disease progression are limited. Pluripotent stem cell technology has facilitated the generation of highly complex models, allowing the study of control and patient-derived microglia in vitro . Moreover, the ability to generate brain organoids that can mimic the 3D tissue environment and intercellular interactions in the brain provide powerful tools to study cellular pathways under homeostatic conditions and various disease pathologies. In this review, we summarise the most recent developments in modelling degenerative diseases and glioblastoma, with a focus on brain organoids with integrated microglia. We provide an overview of the most relevant research on intercellular interactions of microglia to evaluate their potential to study brain pathologies. The immune system plays a key role in different CNS diseases, but current 2D models fail to reproduce the dimensions of cell-cell interactions. Furthermore, brain organoids lack non-neuronal cells. iPSC-derived microglia can be integrated into (1) cerebral organoids to study different pathological contexts including neurodegenerative diseases as well as inflammation after local or global injury, or (2) patient-derived glioblastoma oncospheres to better reproduce the brain environment and research the involvement of microglia in brain cancer. Image created with Biorender. • Modelling microglial function is a growing field with technical culprits to overcome. • Microglia integrated into 3D models allow studies on microglial interactions with CNS-resident cells. • Integrated microglia can respond to local and global organoid damage. • iPSC-derived microglia-containing organoids can shed light on microglial implications in disease pathology.