Patterning of brain organoids derived from human pluripotent stem cells

Zhang, Zhijian; O’Laughlin, Richard; Song, Hongjun; Ming, Guo Li

doi:10.1016/j.conb.2022.102536

Cited by 17 publications

(10 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2E, Timing panel). However, when exposing the organoids to FGF8 for a longer time (concentration experiments), we observed depletion of telencephalic fates at later time points (day [12][13][14][15][16][17][18][19][20], in contrast to robust enrichment in early timepoints (day 3-14) (Fig. 2B and 2E, Concentrations panel).…”

Section: Effect Of Morphogen Timing and Concentration On Regional Cel...mentioning

confidence: 99%

See 1 more Smart Citation

Decoding morphogen patterning of human neural organoids with a multiplexed single-cell transcriptomic screen

Sanchís-Calleja,

Jain,

et al. 2024

Preprint

View full text Add to dashboard Cite

Morphogens, secreted signaling molecules that direct cell fate and tissue development, are used to instruct neuroepithelium to differentiate towards discrete brain region identities. Neural tissues derived from pluripotent stem cells in vitro (neural organoids) provide new models for studying brain region development, however, we lack a comprehensive survey of how the developing human neuroepithelium responds to morphogen cues. Here, we produce a detailed map of morphogen-induced effects on the axial and regional specification of human neural organoids using a multiplexed single-cell transcriptomics screen. We find that the timing, concentration, and combination of morphogens strongly influence organoid cell type and regional composition, and that cell line and neural induction method strongly impact the response to a given morphogen condition. We apply concentration gradients in microfluidic chips or a range of static concentrations in multi-well plates to explore how human neuroepithelium interprets morphogen concentrations and observe similar dose-dependent induction of patterned domains in both scenarios. Altogether, we provide a detailed resource that supports the development of new regionalized neural organoid protocols and enhances our understanding of human central nervous system patterning.

show abstract

Section: Effect Of Morphogen Timing and Concentration On Regional Cel...mentioning

confidence: 99%

“…When supplying BMP4 over an extended period of time (days [12][13][14][15][16][17][18][19][20], increase in concentration led to consistent increase in the percentage of retinal progenitors, while the proportion of NNE cells remained unchanged (Fig. 2B, Fig.…”

Section: Effect Of Morphogen Timing and Concentration On Regional Cel...mentioning

confidence: 99%

Decoding morphogen patterning of human neural organoids with a multiplexed single-cell transcriptomic screen

Sanchís-Calleja,

Jain,

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“… 11 These three‐dimensional models can be derived from human embryonic stem cells (hESCs) or induced human pluripotent stem cells (hiPSCs), often starting from more homogeneous primitive neuroectoderm to more complex and intricate neuronal architecture. 12 The brain organoids have immediate applications in modeling infectious diseases, for example, cerebral organoids were applied to study the impact of the Zika virus on human brain development, which solidified the causal link between Zika infection and microcephaly. 13 At the beginning of the pandemic, brain region‐specific organoids, including the hippocampus, hypothalamus, midbrain, cerebral cortex, and ChP, were employed to probe the neurotropic features of severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) virus and its potential association with a spectrum of neurological symptoms.…”

Section: Introductionmentioning

confidence: 99%

“…Human brain organoids with self‐organized architecture 10 provide powerful tools to explore human brain development and neurological disorders 11 . These three‐dimensional models can be derived from human embryonic stem cells (hESCs) or induced human pluripotent stem cells (hiPSCs), often starting from more homogeneous primitive neuroectoderm to more complex and intricate neuronal architecture 12 . The brain organoids have immediate applications in modeling infectious diseases, for example, cerebral organoids were applied to study the impact of the Zika virus on human brain development, which solidified the causal link between Zika infection and microcephaly 13 .…”

Section: Introductionmentioning

confidence: 99%

Microglia innate immune response contributes to the antiviral defense and blood–CSF barrier function in human choroid plexus organoids during HSV‐1 infection

Qiao

Chiu

Liang

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

The choroid plexus (ChP) is the source of cerebrospinal fluid (CSF). The ChP-CSF system not only provides the necessary cushion for the brain but also works as a sink for waste clearance. During sepsis, pathogens and host immune cells can weaken the ChP barrier and enter the brain, causing cerebral dysfunctions known as sepsisassociated encephalophagy. Here, we used human ChP organoid (ChPO) to model herpes simplex virus type 1 (HSV-1) infection and found ChP epithelial cells were highly susceptible to HSV-1. Since the current ChPO model lacks a functional innate immune component, particularly microglia, we next developed a new microgliacontaining ChPO model, and found microglia could effectively limit HSV-1 infection and protect epithelial barrier in ChPOs. Furthermore, we found the innate immune cyclic GMP-AMP synthase (cGAS)-STING pathway and its downstream interferon response were essential, as cGAS inhibitor RU.512 or STING inhibitor H-151 abolished microglia antiviral function and worsened ChP barrier in organoids. These results together indicated that cGAS-STING pathway coordinates antiviral response in ChP and contributes to treating sepsis or related neurological conditions.

show abstract

“…In this study, we leverage the recent developments in the generation of brain region-specific organoids (Zhang et al 2022) to create a human model of PCH2a. We identified three individuals that display the genetic, clinical and brain imaging features previously described for PCH2a and derived induced pluripotent stem cells (iPSCs) from donated fibroblasts (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Human organoid model of PCH2a recapitulates brain region-specific pathology

Kagermeier

Hauser

Sarieva

et al. 2022

Preprint

View full text Add to dashboard Cite

Pontocerebellar hypoplasia type 2 a (PCH2a) is a rare, autosomal recessive neurogenetic disorder. Affected individuals present with early and severe neurological impairment. The anatomical hallmark of PCH2a is the hypoplasia of the cerebellum and pons accompanied by progressive microcephaly over the first years of life (OMIM #277470). Treatment options are limited and symptomatic. PCH2a results from a homozygous founder variant in the TSEN54 gene (OMIM *608755), which encodes a tRNA splicing endonuclease complex subunit. A recent study revealed altered tRNA pools in fibroblasts from affected individuals with PCH2a. However, the pathological mechanism underlying the hypoplasia of the cerebellum and the progressive microcephaly is unknown due to a lack of a model system. Leveraging recent progress in organoid generation, we developed human models of PCH2a using brain region-specific organoids. We, therefore, obtained skin biopsies from three affected males with genetically confirmed PCH2a and derived induced pluripotent stem cells (iPSCs). Cerebellar and neocortical organoids were differentiated from control and affected iPSCs and showed expression of TSEN54. In line with neuroimaging findings in affected individuals, PCH2a cerebellar organoids are reduced in size compared to controls starting early in differentiation. While neocortical PCH2a organoids also show growth deficits, they are less pronounced than those in cerebellar organoids, reminiscent of the progressive microcephaly in PCH2a. In addition, we do not find evidence of increased apoptosis in PCH2a organoids compared to controls in contrast to what has been suggested in loss-of-function animal models. We have generated a human model of PCH2a, which will allow to decipher disease mechanisms in depth in order to explain how a variant in a ubiquitously expressed gene involved in tRNA metabolism causes pathology in specific brain regions.

show abstract

Patterning of brain organoids derived from human pluripotent stem cells

Cited by 17 publications

References 75 publications

Decoding morphogen patterning of human neural organoids with a multiplexed single-cell transcriptomic screen

Decoding morphogen patterning of human neural organoids with a multiplexed single-cell transcriptomic screen

Microglia innate immune response contributes to the antiviral defense and blood–CSF barrier function in human choroid plexus organoids during HSV‐1 infection

Human organoid model of PCH2a recapitulates brain region-specific pathology

Contact Info

Product

Resources

About