Introduction 19 1 microglia, and Nasu-Hakola disease (Sasaki, 2017). But allogeneic hematopoetic stem cell transplantation (HSCT), thought to replace microglia, has been shown successful in other white matter disorders, specifically in the cerebral from of X-linked adrenoleukodystrophy, metachromatic leukodystrophy and Krabbe disease. This shows the potential involvement of microglia in more leukodystrophies and the potential of microglia as therapeutic strategy (Page et al., 2019). The human brain comprises highly specialized cell types with diverse functions and complex interactions. Although oligodendrocytes are likely central to 4H-associated hypomyelination, it is essential to consider the broader neural network, including neurons, astrocytes, and microglia as these have proven to be deficient in other genetic white matter disorders. Understanding how these cell types interact in 4H could provide valuable insight into the mechanisms underlying 4H leukodystrophy and guide the development of therapeutic strategies. IPSC-DERIVED MODELS FOR 4H RESEARCH Given the limited availability of patient-derived brain tissue, human-induced pluripotent stem cells (hiPSCs) provide a valuable platform for modelling 4H leukodystrophy. Since 4H pathology originates during early brain development, our in vitro models focus on recapitulating key developmental stages through directed differentiation protocols. These include generating relevant brain cell types using classical patterning protocols, creating co-cultures, and establishing three-dimensional (3D) brain organoids. Classical Patterning for Directed Differentiation Classical patterning protocols aim to recapitulate embryonic development by exposing pluripotent stem cells to specific molecular cues that guide them toward neural fates. This method allows the generation of cell types at sequential developmental stages, reflecting the physiological processes occurring during early brain development. For example, dual SMAD inhibition using dorsomorphin and SB431542 is commonly used to promote neural lineage commitment, inducing a neuroectodermal fate that serves as a starting point for neuronal and glial cell lineages (Nadadhur et al., 2017; Shi et al., 2012). While classical patterning is slow compared to overexpression protocols it preserves the natural progression of cell maturation, making it a valuable tool for studying disorders that manifest during specific developmental stages, such as 4H (Zhang et al., 2013) (Yang et al., 2017).
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