The versatile applications of human pluripotent stem cell-derived microglia and microglia-containing brain organoids

Microglia are the resident immune cells of the central nervous system (CNS) and play pivotal roles in nervous development, homeostasis, and various neurological diseases. Most of the previous understanding of microglia came from rodents or a limited number of postmortem microglia. However, as significant differences between murine and human microglia have been verified, it has become increasingly apparent that rodents cannot accurately recapitulate human genetics and pathology, thus hindering the translation of microglial findings from rodents to humans. In addition, primary human microglia are notoriously difficult to obtain and lack the scalability required for many high-throughput assays. Fortunately, recent advances in microglia generation from human pluripotent stem cells (hPSCs) have enabled exciting new avenues to decipher or revisit microglial biology in the human context. Given the complex interactions between microglia and other CNS cells, hPSC-derived microglia-like cells (MGLs) were further engrafted within hPSC-derived brain organoids (BOs), which largely lack microglia due to their different embryonic origins, to study human microglial functions in either health and disease state closer to brain microglia. This is a rapidly evolving field, especially in the last five years, that has begun to yield novel insights into the genetics of human microglia and their unique role in neurological diseases. In this review, we will summarize the versatile applications of hPSC-derived MGLs and microglia-containing BOs. Specifically, we will discuss their applications in disease modeling, omics and systematic analysis, interaction with other CNS cell types, as well as transplantation-based human-mouse chimerism.