Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids

Попова, Галина; Soliman, Sarah S.; Kim, Chang N.; Keefe, Matthew G.; Hennick, Kelsey M.; Jain, Samhita; Li, Tao; Tejera, Darío; Shin, David; Chhun, Bryant B.; McGinnis, Christopher S.; Speir, Matthew L; Gartner, Zev J.; Mehta, Shalin B.; Haeussler, Maximilian; Hengen, Keith B.; Ransohoff, Richard R.; Piao, Xiangshu; Nowakowski, Tomasz J.

doi:10.1016/j.stem.2021.08.015

Cited by 113 publications

(128 citation statements)

References 65 publications

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“…Earlier work has characterised the development of neuronal functions in cerebral organoid in single-cell sequencing and functional recordings, and thus consolidated cerebral organoids as a platform that not only recapitulates the tissue architecture of the developing cortex, but also developmental trajectories of maturing neurons and their electrophysiological properties [ 19 , 34 , 35 , 37 ]. In parallel, recent publications report several strategies of including microglia in the organoids, making it a radically more complete platform to model CNS in vitro [ 54 , 55 , 56 , 58 , 65 ]. These two lines of exploration convened in a very recent report that benchmarked the impact of incorporated primary microglia on the transcriptome and electrophysiological properties of cerebral organoids [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…In parallel, recent publications report several strategies of including microglia in the organoids, making it a radically more complete platform to model CNS in vitro [ 54 , 55 , 56 , 58 , 65 ]. These two lines of exploration convened in a very recent report that benchmarked the impact of incorporated primary microglia on the transcriptome and electrophysiological properties of cerebral organoids [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…Earlier work in characterising the fundamental neurophysiological properties of organoids in absence of microglia have addressed the maturation of sodium/potassium currents [ 22 , 30 ], sustained firing [ 22 , 59 , 60 ] and synaptic activity [ 22 , 30 , 61 , 62 ] in patch-clamp recordings, and of spontaneous bursting [ 37 , 60 , 62 , 63 , 64 ] and oscillatory activities using MEA recordings [ 64 ]. A very recent electrophysiological report showed that transplantation of human primary microglia to brain organoids (at 15th week in vitro) gave rise to synchronous network burst activity using a single developmental time point read-out [ 65 ].…”

Section: Introductionmentioning

confidence: 99%

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Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids

Fagerlund

Dougalis

Shakirzyanova

et al. 2021

Cells

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids

Fagerlund

Dougalis

Shakirzyanova

et al. 2021

Cells

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“…Interestingly, the treated aggregates also displayed significant increases in mean firing rates, burst rates and synchrony on MEA, which was very similar to acute CSF effects in human ex vivo cortical slices [ 114 ]. Primary human microglia from mid-gestation aborted fetuses were also grafted into cerebral organoids where they were shown to reduce synapse counts through active pruning of excitatory synapses [ 224 ]. The microglia-incorporated organoids displayed a significant increase in synchronous activity on MEA, suggesting that microglial activity contributes to the development of neuronal network function.…”

Section: Hpsc-derived 3d Neuronal Cultures and Organoids On Measmentioning

confidence: 99%

“…The significance of astrocytes to network activity on MEA has been shown [ 94 , 173 ], but future studies are needed to dissect the exact molecular mechanisms by which astrocytes promote network synchronization and how they participate in pathological processes [ 129 ]. It is encouraging that the effects of human primary microglia have already been studied in organoids on MEA [ 224 ], but considering the poor availability of primary microglia, it would be important to extend the MEA studies to hPSC-derived microglia [ 117 , 235 , 238 ]. Furthermore, considering the role of neural inflammation in neurodegenerative diseases and infections such as COVID-19 [ 239 , 240 ], it would be essential to study how microglial activation affects network activity in a human context [ 91 ].…”

Section: Future Directionsmentioning

confidence: 99%

Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays

Pelkonen

Pistono

Klecki

et al. 2021

Cells

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Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have been applied to both human subjects and hPSC-derived brain models. Here, we review the literature on the functional characterization of hPSC-derived two- and three-dimensional brain models with MEAs and examine their network function in physiological and pathological contexts. We also summarize MEA results from the human brain and compare them to the literature on MEA recordings of hPSC-derived brain models. MEA recordings have shown network activity in two-dimensional hPSC-derived brain models that is comparable to the human brain and revealed pathology-associated changes in disease models. Three-dimensional hPSC-derived models such as brain organoids possess a more relevant microenvironment, tissue architecture and potential for modeling the network activity with more complexity than two-dimensional models. hPSC-derived brain models recapitulate many aspects of network function in the human brain and provide valid disease models, but certain advancements in differentiation methods, bioengineering and available MEA technology are needed for these approaches to reach their full potential.

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Microinstrumentation for Brain Organoids

Patel,

Shetty,

Acha

et al. 2024

Adv Healthcare Materials

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Brain organoids are three‐dimensional aggregates of self‐organized differentiated stem cells that mimic the structure and function of human brain regions. Organoids bridge the gaps between conventional drug screening models such as planar mammalian cell culture, animal studies, and clinical trials. They can revolutionize the fields of developmental biology, neuroscience, toxicology, and computer engineering. Conventional microinstrumentation for conventional cellular engineering, such as planar microfluidic chips; microelectrode arrays (MEAs), and optical, magnetic, and acoustic techniques, have limitations when applied to 3D organoids, primarily due to their limits with inherently 2D geometry and interfacing. Hence, there is an urgent need to develop new instrumentation that is compatible with live cell culture techniques and with scalable 3D formats of relevance to organoids. This review discusses conventional planar approaches and emerging 3D microinstrumentation necessary for advanced organoid‐machine interfaces. Specifically, the article surveys recently developed microinstrumentation, including 3D printed and curved microfluidics, 3D and fast‐scan optical techniques, buckling and self‐folding microelectrode arrays, 3D interfaces for electrochemical measurements, and 3D spatially controllable magnetic and acoustic technologies relevant to two‐way information transfer with brain organoids. The article highlights key challenges that must be addressed for robust organoid culture and reliable 3D spatiotemporal information transfer.This article is protected by copyright. All rights reserved

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Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids

Cited by 113 publications

References 65 publications

Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids

Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids

Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays

Microinstrumentation for Brain Organoids

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