Chapter 1 16 some studies, but do not fully recapitulate the complex neurodevelopmental environment of the human brain. Therefore, more physiologically relevant models that mimic early tissue development are needed to investigate cell-specific vulnerabilities in 4H and identify early potential therapeutic targets. HUMAN INDUCED PLURIPOTENT STEM CELLS To overcome these limitations, human pluripotent stem cells have emerged as a powerful alternative. Pluripotent stem cells have the unique ability to self-renew and differentiate into cell types from all three germ layers: endoderm, ectoderm and mesoderm. In vivo, pluripotent cells are found in embryos (Thomson et al., 1998). However, by inducing the overexpression of specific transcription factors, somatic cells can be reprogrammed into a pluripotent state, creating human induced pluripotent stem cells (hiPSCs) (Takahashi et al., 2007). These hiPSCs retain the genetic profile of the donor cells and can be differentiated into virtually any cell type, making them particularly suitable for investigating the molecular and cellular mechanisms underlying 4H leukodystrophy. The versatility of pluripotent stem cells lies in their capacity to generate virtually any cell type through directed differentiation. But now the question emerges, which tissue will be investigated? KEY PLAYERS IN HYPOMYELINATION AND NEUROLOGICAL DEFICITS IN 4H Identifying relevant tissues and cell types is essential for understanding the pathophysiology of 4H leukodystrophy and developing targeted therapies. Since 4H usually is characterized primarily by hypomyelination and associated neurological deficits, our focus is on modelling early brain development—the stage when many patients begin to show their first symptoms. This stage of development aligns with essential neurodevelopmental processes such as gliogenesis, myelination and refinement of synapses and circuits (Zhou et al., 2024). The challenge, however, lies in replicating these highly dynamic processes of human brain development in vitro. To gain meaningful insights into 4H pathophysiology, cellular models must reflect aspects of these complex interactions while enabling the study of individual cell-type vulnerabilities. Hence, we focused on a variety of models that centre around key
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