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Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
GABAergic interneurons originate from the ganglionic eminences of the early embryonic brain. Thus, this specific type of neuron can be derived from hPSCs by directing their differentiation to medial ganglionic eminence (MGE) neural progenitors. Using Sonic Hedgehog (SHH) molecule and agonist of SHH signaling, such as purmorphamine, hPSCs can be induced to become MGE progenitors which further give rise to functional GABAergic interneurons (38,49,50). Whole-cell patch-clamp recordings showed that these neurons robustly fired action potentials, indicating the presence of KV and NaV channels. Moreover, another study observed spontaneous synaptic activities which were almost completely eliminated by GABAA antagonist, bicuculline, indicating primarily GABAergic inhibitory neurotransmission inputs in these cultures (38). It is worth mentioning that functional maturation of these hPSC-derived GABAergic interneurons requires an extended timeline in culture. At week 8 post-differentiation, these neurons were comparatively immature and exhibited broad action potential (AP) half width, small afterhyperpolarization (AHP), and the inability to fire repetitively upon current injection. By week 30 post-differentiation, these cells exhibited mature properties as shown by AP firing properties with faster and consistent AP velocity near threshold firing, smaller AP half-width, and larger AHPs as well as high-frequency repetitive AP firing upon current injection. Spontaneous postsynaptic currents were detected as early as week 8 post-differentiation (49).
Pluripotent stem cells for neurodegenerative disease modeling: an expert view on their value to drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Shi-Dong Chen, Hong-Qi Li, Mei Cui, Qiang Dong, Jin-Tai Yu
Compared to neural cell differentiation in two-dimension formats, the three-dimensional (3D) culture models, are more relevant regarding the spatial network organization of tissues, intercellular interaction, and cell-matrix connections, thus more faithfully recapitulating the physiology and pathology of the human brain. Apart from forming structural and cytoarchitectural aspects of the human brain, they also have the ability to mimic epigenetic and transcriptional profiles of patient-specific-derived cells [53,54]. Lancaster et al. were the first to report that 3D structures can imitate human fetal brain development since the derivation of brain organoids, and they also introduced a series of protocols to generate brain organoids from human PSCs [55]. Although derivation protocols mainly rely on the intrinsic ability of PSCs to self-organize without external growth factors, generating 3D structures of different brain regions, including the cerebral cortex, forebrain, hypothalamus, hippocampus, midbrain, cerebellum, and even the medial ganglionic eminence could be achieved with additional pattering factors [56]. For example, forebrain structure cultivation mainly needs the addition of A83-01 (TGF-β inhibitor), DMP (Reversible AMP-kinase inhibitor), CHIR-9902 (WNT inhibitor), SB-431542 (BMP inhibitor, ALK5, ALK4, ALK7 specific), and Matrigel whereas dorsal cerebral cortex needs SB-431542 (BMP inhibitor, ALK5, ALK4, ALK7 specific), LDN-193189 (BMP inhibitor, ALK1, ALK2, ALK3, ALK6 specific), XAV939 (WNT inhibitor, TNKS specific), Y-27632 (ROCK inhibitor) [57]. Recent studies have advanced this method by which structures of distinct brain regional subtypes can be fused in culture to analyze the dynamics of neuron migration and connectivity in neural networks intentionally [58]. For now, the 3D models have been proved a strong complement for modeling neurodegenerative diseases [59,60].