DECODING INTRINSIC FEATURES OF HUMAN BRAIN MATURATION USING A HUMAN BRAIN ORGANOID MODEL

Human brain maturation extends from late embryonic development until early adolescence¹. Previous mouse models have contributed to the body of knowledge on brain maturation, however, there are species-specific differences between human and mouse brain development^2,3. Here, we aim to study human brain maturation from embryonic to early postnatal life through a long-term human pluripotent stem cell-derived human brain organoid model (hBOs) up to 6-9 months in vitro. Our immunostainings and transcriptomic data show a time-dependent appearance of neuronal and glial subtypes, similar to the in vivo human brain. Comparative analysis between mid-stage (3.5 months) and early stage (1 month) hBOs showed transcriptional shifts consistent with early neuronal maturation, including upregulation of synaptic and cytoskeletal pathways and downregulation of cell cycle-related genes associated with progenitor populations. Moreover, our immunostainings late stage hBOs show the presence of mature neuronal features such as expression of synaptic proteins and presence of synapses, complex mature neuronal dendritic trees, and functional changes in axonal transport and activity patterns in the late stage. We also show the involvement of alternative splicing as an instrumental step in human brain maturation. Among these transcriptomic changes, long-term hBOs exhibit differences in TAU isoform expression, which mimic what is observed in the in vivo human newborn brain.
Thus, our long-term hBO model mimics brain maturation features present in the late stages of human brain development and as such it may be a useful model to study human brain maturation in a dish.