Unraveling the Morphological and Functional Maturation Mechanisms Underlying Human Neural Development Using iPSCs‐Derived Neuronal Model

Emerging human induced pluripotent stem cells (hiPSCs)-based neuronal models are useful for studying human neural development. However, existing protocols for differentiating neurons from hiPSCs generally require extended timeframes, making it difficult to capture the rapid, early stages of neuronal morphogenesis and functional maturation. This study presents an in vitro human neuronal model derived from hiPSCs with rapid morphological and functional maturity, by using the combined small molecules and proteins (SMP) protocol. This SMP-induced, hiPSC-derived neuronal model recapitulates core aspects of human neuronal development, providing a temporally compressed system for studying early neuronal development. On the basis of this model, this study demonstrates that both Cav1.2 and Cav1.3, the two subtypes of L-type voltage-gated calcium channels that mediate calcium ion influx, are essential for early morphogenesis of human neuronal development. Moreover, ECEL1 (endothelin converting enzyme-like 1) is identified as a key regulator of human neuronal functional developmental maturation in the early stage of SMP-induced hiPSCs differentiation. ECEL1 acts through calmodulin 3 (CALM3) to regulate functional assembly and expression of multiple ion channels (e.g., voltage-gated sodium ion channels) in neuronal functional development and maturation. These findings illuminate novel mechanisms underlying the morphogenesis and functional maturation of human neurons that are involved in human brain development.