2018
DOI: 10.1016/j.stem.2018.04.009
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Efficient Generation of CA3 Neurons from Human Pluripotent Stem Cells Enables Modeling of Hippocampal Connectivity In Vitro

Abstract: Despite widespread interest in using human induced pluripotent stem cells (hiPSCs) in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a comprehensive and efficient differentiation paradigm for hiPSCs that generate multiple CA3 pyramidal neuron subtypes as detected by single-cell RNA sequencing (RNA-seq). This differentiation paradigm exhibits characteristics of neuronal network maturation, and rabies virus tracing revealed synaptic connect… Show more

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Cited by 121 publications
(128 citation statements)
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“…The next step is to physically connect region-specific organoids to build a more comprehensive functional system. Studies have demonstrated fusion of distinct brain region-derived organoids, such as the medial ganglionic eminence and cortical areas for the analysis of interneuron migration (Xiang et al, 2017), CA1 and CA3 regions in the hippocampus modeling functional connectivity (Sarkar et al, 2018), and dorsal and ventral forebrain (Birey et al, 2017). As these multiple domain structures self-organize in close proximity and form connections, the dynamic interplay can be analyzed as the human brain develops.…”
Section: D Models Connecting 3d Models To Vasculature and Other Bodymentioning
confidence: 99%
“…The next step is to physically connect region-specific organoids to build a more comprehensive functional system. Studies have demonstrated fusion of distinct brain region-derived organoids, such as the medial ganglionic eminence and cortical areas for the analysis of interneuron migration (Xiang et al, 2017), CA1 and CA3 regions in the hippocampus modeling functional connectivity (Sarkar et al, 2018), and dorsal and ventral forebrain (Birey et al, 2017). As these multiple domain structures self-organize in close proximity and form connections, the dynamic interplay can be analyzed as the human brain develops.…”
Section: D Models Connecting 3d Models To Vasculature and Other Bodymentioning
confidence: 99%
“…Various protocols have been developed to derive neural cells from hPSCs that are most relevant to epilepsy, including cortical-like excitatory neurons, 17,18 cortical-like inhibitory neurons (γ-aminobutyric acid [GABA]-expressing interneurons), [19][20][21] and hippocampallike neurons. 22,112 Recent developments in optimizing the protocols of neural differentiation also make it possible to generate astrocytes, [113][114][115] midbrain dopamine neurons 116,117 and spinal motor neurons 118,119 from hPSCs. Most of these protocols involve the application of small molecules to hPSC monolayers or the forced expression of specific transcription factors.…”
Section: Two-dimensional Neural Differentiationmentioning
confidence: 99%
“…For example, a time-course characterisation of human embryonic or induced pluripotent stem cells that are differentiating into hippocampal neurons could be done by analysing the whole transcriptome at a single-cell level. Given that several protocols for generating dentate gyrus granule cells and hippocampal pyramidal cells are already available in the literature (Sakaguchi et al, 2015;Sarkar et al, 2018;Yu et al, 2014), a single-cell analysis on the celltypes generated during the differentiation process could be readily achieved. Such characterisation approach would not only help us to validate cell-type and stage-specific markers of human neurogenesis but also to develop an accurate understanding of how neurogenesis is affected in the disease context.…”
Section: Limitations and Recommendationsmentioning
confidence: 99%