Modeling Hippocampal Neurogenesis Using Human Pluripotent Stem Cells

Yu, Diana; Giorgio, Francesco Paolo Di; Ye, Jun; Marchetto, Maria C.; Brennand, Kristen J.; Wright, Rebecca N.; Mei, Arianna; McHenry, Lauren; Lisuk, David; Grasmick, Jaeson Michael; Silberman, Pedro; Silberman, Giovanna; Jappelli, Roberto; Gage, Fred H.

doi:10.1016/j.stemcr.2014.06.015

Cited by 64 publications

(101 citation statements)

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“…With this elaborative cytoarchitecture, the neurons gradually matured with synaptic connection formation. We also found a transition from an NMDA receptor to an AMPA receptor mediated transmission of excitatory synapses in our culture system, indicating a maturation process of the neurons that contributes to the formation of a functional circuit (Yu et al, 2014). Together, our vOrganoids that were derived from hESCs with endothelial cells mimic human cortical developmental not only in their cell types and cellular lamination but also in their circuit formation.…”

Section: Discussionsupporting

confidence: 53%

Vascularized human cortical organoids model cortical development in vivo

Sun

Liu

et al. 2019

Preprint

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Modelling the neuronal progenitor proliferation and organization processes that produce mature cortical neuron subtypes is essential for the study of human brain development and the search for potential cell therapies. To provide a vascularized and functional model of brain organoids, we demonstrated a new paradigm to generate vascularized organoids that consist of typical human cortical cell types and recapitulate the lamination of the neocortex with a vascular structure formation for over 200 days. In addition, the observation of the sEPSCs(spontaneous Excitatory Postsynaptic Potential)and sIPSCs(spontaneous Inhibitory Postsynaptic Potential) and the bidirectional electrical transmission indicated the presence of chemical and electrical synapses in the vOrganoids. More importantly, the single-cell RNA-seq analysis illustrated that the vOrganoids exhibited microenvironments to promote neurogenesis and neuronal maturation that resembled in vivo processes. The transplantation of the vOrganoids to the mouse S1 cortex showed human-mouse co-constructed functional blood vessels in the grafts that could promote the survival and integration of the transplanted cells to the host. This vOrganoid culture method could not only serve as a model to study human cortical development and to explore brain disease pathology but could also provide potential prospects for new cell therapies for neural system disorders and injury.

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Section: Discussionsupporting

confidence: 53%

Vascularized human cortical organoids model cortical development in vivo

Sun

Liu

et al. 2019

Preprint

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“…These SZ neurons show elevated levels of activity-dependent secreted catecholamines including dopamine, norepinephrine, and epinephrine (Hook et al, 2014), suggesting a pathological role of aberrant neurotransmitter release in SZ. By differentiating hiPSCs into hippocampal NPCs and neurons, the same group revealed dysregulation of gene expressions in the SZ hippocampal NPCs such as lowered levels of NEU-ROD1, PROX1, and TBR1 (T-Box, Brain 1), and deficits of the neuronal activity and spontaneous neurotransmitter release in SZ hippocampal neurons (Yu et al, 2014), which are consistent with the hippocampal phenotypes observed in patients with SZ, including dysregulated hippocampal neurogenesis and hippocampusassociated cognitive impairments (Reif et al, 2006;Walton et al, 2012). Other groups have also reported that hiPSC-derived neurons from patients with sporadic SZ show enhanced oxidative stress (Paulsen et al, 2012;Robicsek et al, 2013) and abnormal responses to environmental stress (Hashimoto-Torii et al, 2014), suggesting that they may be key components in the pathogenesis of SZ.…”

Section: Schizophreniamentioning

confidence: 97%

“…These area-specific NPCs could be further differentiated into different neuronal subtypes for disease modeling and drug screening, including cortical glutamatergic neurons or cerebral organoids (TBR1 1 /CTIP2 1 /BRN2 1 /SATB2 1 ), cortical GABAergic neurons (GABA 1 /GAD65/67 1 /VGAT 1 /SST 1 /PV 1 ), midbrain DA neurons (TH 1 /NURR1 1 /PITX3 1 /DAT 1 ), and hippocampal granule cells (PROX1 1 ). and NEUROD1 (neuronal differentiation 1) (Yu et al, 2014); and midbrain NPCs, which are positive for NES-TIN, FOXA2 (forkhead box A1), and LMX1A (LIM homeobox transcription factor 1 alpha) Swistowski et al, 2010;Kriks et al, 2011;Ma et al, 2011).…”

Section: D Differentiationmentioning

confidence: 99%

Modeling neurodevelopmental and psychiatric diseases with human iPSCs

Wen

2017

J of Neuroscience Research

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Neurodevelopmental and psychiatric disorders, including autism spectrum disorder and schizophrenia, are complex and heterogeneous disorders that affect a large portion of the world's population. While the causes are still poorly understood, currently available treatments are limited; the development of rational therapeutics based on an understanding of the etiology and pathogenesis of the disease is imperative. The breakthrough technology of deriving induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of healthy subjects or patients, offers an unprecedented opportunity to recapitulate both normal and pathological development of human tissue, thereby opening up a new avenue for disease modeling and drug development in a more genetically tractable and disease-relevant system. Here, I review the recent progress in the use of human iPSCs for modeling neurodevelopmental and psychiatric disorders and developing novel therapeutic strategies, and discuss challenges in this rapidly moving field. © 2017 Wiley Periodicals, Inc.

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“…In parallel, Mariani et al (2012) independently developed a protocol for the generation of cortical glutamatergic neurons by using dual SMAD inhibition, suppression of WNT signaling, and application of FGF2. Yu et al (2014) reported a protocol which used inhibition of BMP, TGF-ß, and WNT signaling together with cyclopamine, Wnt3a, and brain-derived growth factor (BDGF) to induce differentiation into hippocampal dentate gyrus (DG) granule cells. The protocol recapitulates important steps in hippocampal neurogenesis in vivo.…”

Section: Differentiation Into Glutamatergic Neuronsmentioning

confidence: 99%

“…Overview of diverse differentiation protocols used for the generation of neuronal and glia cells Cell type Reference Dopaminergic neuron Chambers et al 2009; Zhang and Zhang 2010;Kriks et al 2011;Kirkeby et al 2012; Denham et al 2012;Xi et al 2012; Doi et al 2014;Adil et al 2017;Fedele et al 2017;Nolbrant et al 2017 Glutamatergic neuronShi et al 2012a, b;Mariani et al 2012;Boisvert et al 2013;Yu et al 2014;Vazin et al 2014; …”

mentioning

confidence: 99%

Induced pluripotent stem cells (iPSCs) as model to study inherited defects of neurotransmission in inborn errors of metabolism

Jung-Klawitter

Opladen

2018

J of Inher Metab Disea

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The ability to reprogram somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human disease. Especially for the modeling of rare human monogenetic diseases with limited numbers of patients available worldwide and limited access to the mostly affected tissues, iPSCs have become an invaluable tool. To study rare diseases affecting neurotransmitter biosynthesis and neurotransmission, stem cell models carrying patient-specific mutations have become highly important as most of the cell types present in the human brain and the central nervous system (CNS), including motoneurons, neurons, oligodendrocytes, astrocytes, and microglia, can be differentiated from iPSCs following distinct developmental programs. Differentiation can be performed using classical 2D differentiation protocols, thereby generating specific subtypes of neurons or glial cells in a dish. On the other side, 3D differentiation into "organoids" opened new ways to study misregulated developmental processes associated with rare neurological and neurometabolic diseases. For the analysis of defects in neurotransmission associated with rare neurometabolic diseases, different types of brain organoids have been made available during the last years including forebrain, midbrain and cerebral organoids. In this review, we illustrate reprogramming of somatic cells to iPSCs, differentiation in 2D and 3D, as well as already available disease-specific iPSC models, and discuss current and future applications of these techniques.

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Modeling Hippocampal Neurogenesis Using Human Pluripotent Stem Cells

Cited by 64 publications

References 0 publications

Vascularized human cortical organoids model cortical development in vivo

Vascularized human cortical organoids model cortical development in vivo

Modeling neurodevelopmental and psychiatric diseases with human iPSCs

Induced pluripotent stem cells (iPSCs) as model to study inherited defects of neurotransmission in inborn errors of metabolism

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