Microglia innately develop within cerebral organoids

Abstract

Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

“…Studies suggest that the possible mechanism underlying neurodegeneration is the chronic inflammation of the CNS induced by the activation of microglia (4,5). Actually, microglia are the resident innate immune cells of the CNS, which originate from the mesoderm lineage and provide innate immunity in the brain (6). Impaired interaction between microglia and DA neurons is increasingly being linked to PD.…”

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

“…Interestingly, a recent study demonstrated that the original Lancaster protocol was perhaps capable of doing this all along (Ormel et al, ). In this report, organoid‐grown microglia (oMGs) were shown to innately develop within BORGs, with only limited alterations to the original protocol published by Lancaster et al ().…”

“…While this makes the model well suited for the study of neurodevelopmental disorders, such as autism (Mariani et al, ; P. Wang et al, ), schizophrenia (Ye et al, ), or ZIKA transmission (Muffat et al, ), it also presents problems when attempting to utilize BORGs and oMGs to study diseases that require a more mature brain environment, such as PD or AD. Ormel et al () also demonstrated that oMGs display a diminished expression levels of the key microglia genes P2RY12 and TMEM119 , further suggesting that these cells have not completely obtained a mature, homeostatic signature. However, this does not mean that oMGs are entirely inappropriate for studying diseases of the developing brain, as it has been shown that the transcriptome may begin to mature as BORGs are aged (Pasca et al, ; Quadrato et al, ).…”

“…Therefore, for the sake of simplicity, we will refer to all in vitro iPSC‐derived microglia as iMGs regardless of the differentiation protocol used to generate the cells. Additionally, we will refer to derivatives of this methodology as oMGs, for cerebral organoid microglia, and xMGs, for xenotransplanted microglia, as each of these terms have already been published in the literature (Hasselmann et al, ; Ormel et al, ; Xiang et al, ).…”

Concise Review: Modeling Neurodegenerative Diseases with Human Pluripotent Stem Cell-Derived Microglia

“…Ormel et. al found that microglia innately develop within iPSC‐derived cerebral organoids and showed that those microglia perform similar as primary human microglia in functional assays . Their cerebral organoid protocol is omitting non‐neuronal linage suppression.…”