Abstract
Glia are present in all organisms with a central nervous system but considerably differ in their diversity, functions, and numbers. Coordinated efforts across many model systems have contributed to our understanding of glial-glial and neuron-glial interactions during nervous system development and disease, but human glia exhibit prominent species-specific attributes. Limited access to primary samples at critical developmental timepoints constrains our ability to assess glial contributions in human tissues. This challenge has been addressed throughout the past decade via advancements in human stem cell differentiation protocols that now offer the ability to model human astrocytes, oligodendrocytes, and microglia. Here, we review the use of novel 2D cell culture protocols, 3D organoid models, and bioengineered systems derived from human stem cells to study human glial development and the role of glia in neurodevelopmental disorders.
Highlights
Glia are essential constituents and regulators of the central nervous system (CNS), and studies from the past several decades have illuminated their immense importance to brain development in both health and disease (Allen and Lyons, 2018)
Following early methods to successfully differentiate murine ESCs into cells of the neuronal lineage (Tropepe et al, 2001), similar approaches were sought to generate astrocytes. Many of these astrocyte differentiation protocols from human stem cells are outlined in Table 3 of Chandrasekaran et al (2016), but here we summarize the general logic amongst popular protocols with a particular focus on those that are new within the past 5 years
Organoids have aided in advancing cellular complexity and long-term maturation studies, the diversity in cell types and ability to produce fully mature cells still does not match the complexity of the human brain (Bhaduri et al, 2020)
Summary
Glia are essential constituents and regulators of the central nervous system (CNS), and studies from the past several decades have illuminated their immense importance to brain development in both health and disease (Allen and Lyons, 2018). We summarize current 2D, 3D, and bioengineered human stem cell-derived models of astrocytes, OLs, and microglia and how these models are used to study the contributions of glia to NDDs. There are two primary classes of CNS glia, each with unique developmental origins: macroglia and microglia. During human fetal CNS development, neural stem cells (radial glia) differentiate first into neurons and astrocytes and OLs in a temporally restricted sequence. Insulin-like growth factor 1 (IGF1) has been shown to promote oligodendrogenesis and myelination through its receptor signaling cascade (Zeger et al, 2007) These examples are a small subset of the factors that drive the gliogenic switch during development, reviewed extensively in Miller and Gauthier (2007) and Okano and Temple (2009), and are the same signaling molecules and TFs that have been repurposed to drive in vitro astrocyte and OL differentiation from human stem cells. This leads to uncertainty to whether some genes implicated in neurological disorders in humans behave and interact in nonhuman model systems
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