hPSC-derived microglia shape neuronal morphology and enhance network activity in vitro 157 5 INTRODUCTION Human pluripotent stem cell (hPSC) technologies have revolutionized neuroscience by enabling generation of human- and patient-specific neuronal cultures. This has facilitated the development of advanced disease models for neurodegenerative and neurodevelopmental disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and autism spectrum disorders. Initially, research primarily focused on neuron-only cultures, but more recent efforts have incorporated glial cell populations, such as astrocytes, oligodendrocytes and microglia in both 2D or 3D culture systems (Gordon & Geschwind, 2020; Kim et al., 2015; Slanzi et al., 2020). These glial cells are critical to brain development, homeostasis, and the maintenance of neuronal networks. Moreover, there is growing recognition of their roles in the pathology of neurodegeneration and neurodevelopmental diseases (Colonna & Butovsky, 2017; Molofsky et al., 2012). Microglia, in particular, have garnered increasing attention due to their roles as key regulators of synaptic pruning, neuroinflammation, and debris clearance (Paolicelli & Ferretti, 2017). Dysregulation of microglial function has been implicated in the progression of several neurodegenerative conditions, including AD and PD (Leng & Edison, 2021; Poppell et al., 2023), but also in leukodystrophies. Particularly for adrenoleukodystrophy (ALD), there is a specific suspicion for microglia involvement since ALD is caused by mutations in ABCD1, a gene that is highly expressed in microglia. Additionally, the positive results of early hematopoietic stem cell transplantation (HSCT) point towards a role for microglia (Aubourg et al., 1990). Although leukodystrophies share common pathology, microglia involvement is not described in all leukodystrophies. For 4H leukodystrophy, which is caused by mutations in genes coding for subunits of RNA polymerase III, no association with impaired microglia is made yet. However, RNA polymerase III is utilized in all cell types, hence microglia might still play a role in disease pathology. The progressive nature of leukodystrophies and the lack of curative treatment options stress the need to elucidate the role of microglia in these diseases, hence the quest to include microglia in in vitro models of leukodystrophies (Bonkowsky et al., 2010; Bonkowsky et al., 2018; Vanderver et al., 2012). Recent advancements in hPSC technology now allow derivation of microglia-like cells from hPSCs. However, co-culture systems that integrate microglia-like cells with human neurons to study their interactions and their impact on neuronal network development remain limited. The absence of such models restricts our understanding of how microglia influence neural circuit dynamics and contribute to both normal brain function and disease pathology.
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