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Article ; Online: Organelle mapping in dendrites of human iPSC-derived neurons reveals dynamic functional dendritic Golgi structures

Jingqi Wang / Maciej Daniszewski / Marlene M. Hao / Damián Hernández / Alice Pébay / Paul A. Gleeson / Lou Fourriere

Cell Reports, Vol 42, Iss 7, Pp 112709- (2023)

2023

Abstract: Summary: Secretory pathways within dendrites of neurons have been proposed for local transport of newly synthesized proteins. However, little is known about the dynamics of the local secretory system and whether the organelles are transient or stable ... ...

Abstract	Summary: Secretory pathways within dendrites of neurons have been proposed for local transport of newly synthesized proteins. However, little is known about the dynamics of the local secretory system and whether the organelles are transient or stable structures. Here, we quantify the spatial and dynamic behavior of dendritic Golgi and endosomes during differentiation of human neurons generated from induced pluripotent stem cells (iPSCs). In early neuronal development, before and during migration, the entire Golgi apparatus transiently translocates from the soma into dendrites. In mature neurons, dynamic Golgi elements, containing cis and trans cisternae, are transported from the soma along dendrites, in an actin-dependent process. Dendritic Golgi outposts are dynamic and display bidirectional movement. Similar structures were observed in cerebral organoids. Using the retention using selective hooks (RUSH) system, Golgi resident proteins are transported efficiently into Golgi outposts from the endoplasmic reticulum. This study reveals dynamic, functional Golgi structures in dendrites and a spatial map for investigating dendrite trafficking in human neurons.
Keywords	CP: Cell biology ; CP: Neuroscience ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Generation of a gene-corrected human isogenic iPSC line from an Alzheimer’s disease iPSC line carrying the London mutation in APP (V717I)

Damián Hernández / Stephanie Morgan Schlicht / Maciej Daniszewski / Celeste M. Karch / Alison M. Goate / Alice Pébay

Stem Cell Research, Vol 53, Iss , Pp 102373- (2021)

2021

Abstract: We report the genome-editing of an existing iPSC line carrying the London mutation in APP (V717I) into an iPSC line in which the pathogenic mutation was corrected. The resulting isogenic iPSC line maintained pluripotent stem cell morphology, a normal ... ...

Abstract	We report the genome-editing of an existing iPSC line carrying the London mutation in APP (V717I) into an iPSC line in which the pathogenic mutation was corrected. The resulting isogenic iPSC line maintained pluripotent stem cell morphology, a normal karyotype, expression of pluripotency markers and the ability to differentiate into the three germ-layers in vitro.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Efficacy of Laropiprant in Minimizing Brain Injury Following Experimental Intracerebral Hemorrhage

Abdullah Shafique Ahmad / Monique Mendes / Damian Hernandez / Sylvain Doré

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 10

Abstract: Abstract Intracerebral hemorrhage (ICH) is one of the most devastating and disabling forms of stroke, yet effective treatments are still lacking. Prostaglandins and their receptors have been implicated in playing vital roles in ICH outcomes. Recently, ... ...

Abstract	Abstract Intracerebral hemorrhage (ICH) is one of the most devastating and disabling forms of stroke, yet effective treatments are still lacking. Prostaglandins and their receptors have been implicated in playing vital roles in ICH outcomes. Recently, laropiprant, a DP1 receptor antagonist, has been used in combination with niacin to abolish the prostaglandin D2-(PGD2)-induced flushing. Here, we test the hypothesis that laropiprant limits bleeding and rescues the brain from ICH. Wildtype (WT) and DP1−/− mice were subjected ICH and neurologic deficits and hemorrhagic lesion outcomes were evaluated at 72 hours after the ICH. To test the therapeutic potential of laropiprant, WT mice subjected to ICH were treated with laropiprant at 1 hour after the ICH. The putative effect of laropiprant on limiting hematoma expansion was tested by an in vivo tail bleeding cessation method and an ex vivo coagulation method. Finally, the roles of laropiprant on gliosis and iron accumulation were also investigated. A significant decrease in the injury volume was observed in DP1−/− as well as laropiprant-treated WT mice. The tail bleeding time was significantly lower in laropiprant group as compared with the vehicle group. Significantly lower Iba-1 and Perls’ iron staining in DP1−/− and laropiprant-treated WT groups were observed. Altogether, the data suggest that laropiprant treatment post-ICH attenuates brain damage by targeting primary as well as secondary injuries.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids

Ilkka Fagerlund / Antonios Dougalis / Anastasia Shakirzyanova / Mireia Gómez-Budia / Anssi Pelkonen / Henna Konttinen / Sohvi Ohtonen / Mohammad Feroze Fazaludeen / Marja Koskuvi / Johanna Kuusisto / Damián Hernández / Alice Pebay / Jari Koistinaho / Tuomas Rauramaa / Šárka Lehtonen / Paula Korhonen / Tarja Malm

Cells, Vol 11, Iss 124, p

2022 Volume 124

Abstract: Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral ... ...

Abstract	Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral organoids. Here we show that erythromyeloid progenitors (EMPs), differentiated from induced pluripotent stem cells, migrate to cerebral organoids, and mature into microglia-like cells and interact with synaptic material. Patch-clamp electrophysiological recordings show that the microglia-like population supported the emergence of more mature and diversified neuronal phenotypes displaying repetitive firing of action potentials, low-threshold spikes and synaptic activity, while multielectrode array recordings revealed spontaneous bursting activity and increased power of gamma-band oscillations upon pharmacological challenge with NMDA. To conclude, microglia-like cells within the organoids promote neuronal and network maturation and recapitulate some aspects of microglia-neuron co-development in vivo, indicating that cerebral organoids could be a useful biorealistic human in vitro platform for studying microglia-neuron interactions.
Keywords	cerebral organoid ; microglia ; neurogenesis ; neuronal function ; development ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A village in a dish model system for population-scale hiPSC studies

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 12

Abstract: Abstract The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and different conditions. Human induced pluripotent stem cells are uniquely suited ... ...

Abstract	Abstract The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and different conditions. Human induced pluripotent stem cells are uniquely suited to study these context-dependent effects but cell lines from hundreds or thousands of individuals are required. Village cultures, where multiple induced pluripotent stem lines are cultured and differentiated in a single dish, provide an elegant solution for scaling induced pluripotent stem experiments to the necessary sample sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned to an induced pluripotent stem line using single-cell sequencing and illustrating that the genetic, epigenetic or induced pluripotent stem line-specific effects explain a large percentage of gene expression variation for many genes. We demonstrate that village methods can effectively detect induced pluripotent stem line-specific effects, including sensitive dynamics of cell states.
Keywords	Science ; Q
Subject code	612
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transcriptomes and neurotransmitter profiles of classes of gustatory and somatosensory neurons in the geniculate ganglion

Gennady Dvoryanchikov / Damian Hernandez / Jennifer K. Roebber / David L. Hill / Stephen D. Roper / Nirupa Chaudhari

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 16

Abstract: Characterization of gustatory neural pathways has suffered due to a lack of molecular markers. Here, the authors report single cell RNA sequencing and unbiased transcriptome analyses to reveal major distinctions between gustatory and somatosensory ... ...

Abstract	Characterization of gustatory neural pathways has suffered due to a lack of molecular markers. Here, the authors report single cell RNA sequencing and unbiased transcriptome analyses to reveal major distinctions between gustatory and somatosensory neurons and subclusters of gustatory neurons with unique molecular and functional profiles.
Keywords	Science ; Q
Language	English
Publishing date	2017-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mitochondrial Fusion by M1 Promotes Embryoid Body Cardiac Differentiation of Human Pluripotent Stem Cells

Jarmon G. Lees / Anne M. Kong / Yi C. Chen / Priyadharshini Sivakumaran / Damián Hernández / Alice Pébay / Alexandra J. Harvey / David K. Gardner / Shiang Y. Lim

Stem Cells International, Vol

2019 Volume 2019

Abstract: Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal ... ...

Abstract	Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal cardiac lineages. Inhibiting mitochondrial fission has been shown to promote cardiac differentiation of iPSCs. However, the effect of hydrazone M1, a small molecule that promotes mitochondrial fusion, on cardiac mesodermal commitment of human iPSCs is unknown. Here, we demonstrate that treatment with M1 promoted mitochondrial fusion in human iPSCs. Treatment of iPSCs with M1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. The pro-fusion and pro-cardiogenic effects of M1 were not associated with changes in expression of the α and β subunits of adenosine triphosphate (ATP) synthase. Our findings demonstrate for the first time that hydrazone M1 is capable of promoting cardiac differentiation of human iPSCs, highlighting the important role of mitochondrial dynamics in cardiac mesoderm lineage specification and cardiac development. M1 and other mitochondrial fusion promoters emerge as promising molecular targets to generate lineages of the heart from human iPSCs for patient-specific regenerative medicine.
Keywords	Internal medicine ; RC31-1245
Subject code	610
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Simple Differentiation Protocol for Generation of Induced Pluripotent Stem Cell-Derived Basal Forebrain-Like Cholinergic Neurons for Alzheimer’s Disease and Frontotemporal Dementia Disease Modeling

Sonia Sanz Muñoz / Martin Engel / Rachelle Balez / Dzung Do-Ha / Mauricio Castro Cabral-da-Silva / Damian Hernández / Tracey Berg / Jennifer A. Fifita / Natalie Grima / Shu Yang / Ian P. Blair / Garth Nicholson / Anthony L. Cook / Alex W. Hewitt / Alice Pébay / Lezanne Ooi

Cells, Vol 9, Iss 2018, p

2020 Volume 2018

Abstract: The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter ... ...

Abstract	The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain-like cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.
Keywords	induced pluripotent stem cells ; disease modelling ; neuronal differentiation ; cholinergic neurons ; Alzheimer’s disease ; frontotemporal dementia ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Single cell eQTL analysis identifies cell type-specific genetic control of gene expression in fibroblasts and reprogrammed induced pluripotent stem cells

Drew Neavin / Quan Nguyen / Maciej S. Daniszewski / Helena H. Liang / Han Sheng Chiu / Yong Kiat Wee / Anne Senabouth / Samuel W. Lukowski / Duncan E. Crombie / Grace E. Lidgerwood / Damián Hernández / James C. Vickers / Anthony L. Cook / Nathan J. Palpant / Alice Pébay / Alex W. Hewitt / Joseph E. Powell

Genome Biology, Vol 22, Iss 1, Pp 1-

2021 Volume 19

Abstract: Abstract Background The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) has provided a foundation for in vitro human disease modelling, drug development and population genetics studies. Gene expression plays a ... ...

Abstract	Abstract Background The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) has provided a foundation for in vitro human disease modelling, drug development and population genetics studies. Gene expression plays a critical role in complex disease risk and therapeutic response. However, while the genetic background of reprogrammed cell lines has been shown to strongly influence gene expression, the effect has not been evaluated at the level of individual cells which would provide significant resolution. By integrating single cell RNA-sequencing (scRNA-seq) and population genetics, we apply a framework in which to evaluate cell type-specific effects of genetic variation on gene expression. Results Here, we perform scRNA-seq on 64,018 fibroblasts from 79 donors and map expression quantitative trait loci (eQTLs) at the level of individual cell types. We demonstrate that the majority of eQTLs detected in fibroblasts are specific to an individual cell subtype. To address if the allelic effects on gene expression are maintained following cell reprogramming, we generate scRNA-seq data in 19,967 iPSCs from 31 reprogramed donor lines. We again identify highly cell type-specific eQTLs in iPSCs and show that the eQTLs in fibroblasts almost entirely disappear during reprogramming. Conclusions This work provides an atlas of how genetic variation influences gene expression across cell subtypes and provides evidence for patterns of genetic architecture that lead to cell type-specific eQTL effects.
Keywords	Expression quantitative trait loci (eQTLs) ; Single cell RNA-sequencing (scRNA-seq) ; Induced pluripotent stem cells (iPSCs) ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	612
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma

Maciej Daniszewski / Anne Senabouth / Helena H. Liang / Xikun Han / Grace E. Lidgerwood / Damián Hernández / Priyadharshini Sivakumaran / Jordan E. Clarke / Shiang Y. Lim / Jarmon G. Lees / Louise Rooney / Lerna Gulluyan / Emmanuelle Souzeau / Stuart L. Graham / Chia-Ling Chan / Uyen Nguyen / Nona Farbehi / Vikkitharan Gnanasambandapillai / Rachael A. McCloy /

Linda Clarke / Lisa S. Kearns / David A. Mackey / Jamie E. Craig / Stuart MacGregor / Joseph E. Powell / Alice Pébay / Alex W. Hewitt

Cell Genomics, Vol 2, Iss 6, Pp 100142- (2022)

2022

Abstract: Summary: To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal ... ...

Abstract	Summary: To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.
Keywords	human induced pluripotent stem cells ; retinal organoids ; retinal ganglion cells ; single-cell RNA sequencing ; glaucoma ; transcriptomics ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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