Recently, the research team of Professor Meng Qingtuan from the Multi-omics Research Center for Brain Diseases of the First Affiliated Hospital of University of South China published a review paper titled “Microglia-containing human brain organoids for the study of brain developmentpathology” in Molecular Psychiatry (IF =13.4, JCR Q1), a top journal in the field of mental diseases. The First Affiliated Hospital of University of South China is the primary affiliation, with Dr. Zhang Wendiao (a jointly trained doctoral student by Central South UniversityUniversity of South China)Dr. Jiang Jiamei as the co-first authors of the paper. Prof. Meng Qingtuan (the First Affiliated Hospital of University of South China), Prof. Chen Chao (Central South University),Professor Liu Chunyu (SUNY Upstate Medical University) are the co-corresponding authors.
Microglia are essential immune cells in the brain, playing important roles in neural developmentthe maintenance of brain homeostasis. Abnormalities in their functions have been found to be related to various brain diseases such as neurodegenerative diseasesmental illnesses. Studying the functions of microglia helps to reveal the pathogenesis of brain diseasesdevelop corresponding therapeutic drugs.
This review introduced the commonly used models for microglia research, such as 2D cell culture modelsanimal models. However, these models usually lack the human genetic backgroundthe interaction between microgliaother human brain cells, failing to accurately simulate the characteristics of microglia in vivo. In recent years, the emergence of the newly developed 3D human brain organoids (HBOs) has provided a powerful research model for the field of neuroscience. During the formation of HBOs, the differentiation of cellsmesodermendoderm usually needs to be inhibited,since microglia originate from the mesoderm, HBOs are generally considered not to contain microglia. Currently, some studies have established human brain organoids containing microglia (MC-HBOs) using different strategies. This review focuses on four methods for establishing MC-HBOs models (1. Co-culturing microgliaHBOs; 2. Co-culturing microglia progenitor cellsHBOs; 3. Co-culturing microglia progenitor cellsneural progenitor cells; 4. Spontaneous formation of microglia in HBOs), their advantages, disadvantages,applications.
Finally, the authors summarizedprospected the MC-HBOs model, highlighting the advantages of MC-HBOs in simulating the characteristics of the human brainmicroglia in vivo,emphasizing that it serves as a powerful tool for studying human brain development, disease mechanisms, immune inflammation,gene function. However, MC-HBOs are essentially in vitro cell modelsstill lack blood vesselsthe in vivo microenvironment, failing to fully simulate the structurecharacteristics of the human brain. Moreover, MC-HBOs established by different methods exhibit significant heterogeneity in the maturity of microgliabrain-like organoids, making it particularly important to standardize the definition of brain-like organoidsthe identification of microglia identityfunction. Ultimately, the authors believe that air-liquid interface culture, vascular systems,microfluidic systems can help reduce cell stress responses in brain-like organoidscontribute to the maturation of organoids. In particular, transplanting MC-HBOsthe mouse brain can address some of the defects of brain-like organoidsanimal models, making it a promising neweffective research model.
In addition, in March of this year, the research team of Professor Meng Qingtuan published a research article titled “Human forebrain organoids reveal connections between valproic acid exposureautism risk” in the international academic journal Translational Psychiatry (IF=8.0, JCR Q1). The First Affiliated Hospital of University of South China serves as the primary affiliation, with Professor Meng Qingtuan as the first author,Professor Tang BeishaCentral South University’s Professor Chen Chao as co-corresponding authors.
Exposure to valproic acid (VPA) during pregnancy, as an environmental factor, can increase the risk of autism spectrum disorder (ASD) in offspring. However, the mechanism of action of VPA in the human brain remains to be studied. This study used human forebrain organoids (hFOs) as a modelutilized RNA sequencing to discover that VPA primarily affects the expression of genes related to neural development, synaptic transmission, oxytocin signaling,calciumpotassium signaling pathways. These VPA-regulated genes significantly overlap with known ASD risk-related genes. Further single-cell RNA sequencing revealed that VPA mainly affects the expression of genes in the choroid plexus, excitatory neurons, immature neurons,medial ganglionic eminence cells in hFOs. Through the MEA microelectrode array experiment, the authors found that VPA exposure disrupts the synaptic signal transmission in hFOs. Based on the hFOs model, this study revealed that VPA exposure can regulate biological functionsgene expression related to ASD under human genetic backgroundin vivo-like conditions, providing a basis for understanding the pathogenesis of ASD.
The above-mentioned research was supported by the National Natural Science Foundation of China, the Outstanding Youth Foundation of Hunan Province, the Hunan Provincial Youth ScienceTechnology Innovation Talent Program. etc.
Link to original article：https://www.nature.com/articles/s41380-022-01892-1 https://www.nature.com/articles/s41398-022-01898-x