Phenotype and Distribution of Immature Neurons in the Human Cerebral Cortex Layer II

Coviello, Simona; Gramuntell, Yaiza; Klimczak, Patrycja; Varea, Emilio; Blasco-Ibáñez, José Miguel; Crespo, Carlos; Gutiérrez, Antonio; Nácher, Juan

doi:10.3389/fnana.2022.851432

Cited by 12 publications

(10 citation statements)

References 59 publications

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“…IPs express the canonical marker EOMES (Englund et al 2005). IP clusters share transcriptomic signatures with neurons (ROBO1 (Ip et al 2011), CUX1 (Coviello et al 2022)), as has been previously reported in organoid scRNA-seq studies (Quadrato et al 2017;Velasco et al 2019). Some neural progenitor cells (NPCs) expressed S phase markers or G2/M phase markers in addition to VIM and PAX6.…”

Section: Organoids Produce Expected Cell Typessupporting

confidence: 59%

Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture

Glass,

Waxman,

Yamashita

et al. 2023

Preprint

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Background: Reproducibility of hCO phenotypes remains a concern for modeling neurodevelopmental disorders. While guided human cortical organoid (hCO) protocols reproducibly generate cortical cell types in multiple cell lines at one site, variability across sites using a harmonized protocol has not yet been evaluated. We present an hCO cross-site reproducibility study examining multiple phenotypes. Methods: Three independent research groups generated hCOs from one induced pluripotent stem cell (iPSC) line using a harmonized miniaturized spinning bioreactor protocol. scRNA-seq, 3D fluorescent imaging, phase contrast imaging, qPCR, and flow cytometry were used to characterize the 3 month differentiations across sites. Results: In all sites, hCOs were mostly cortical progenitor and neuronal cell types in reproducible proportions with moderate to high fidelity to the in vivo brain that were consistently organized in cortical wall-like buds. Cross-site differences were detected in hCO size and morphology. Differential gene expression showed differences in metabolism and cellular stress across sites. Although iPSC culture conditions were consistent and iPSCs remained undifferentiated, primed stem cell marker expression prior to differentiation correlated with cell type proportions in hCOs. Conclusions: We identified hCO phenotypes that are reproducible across sites using a harmonized differentiation protocol. Previously described limitations of hCO models were also reproduced including off-target differentiations, necrotic cores, and cellular stress. Improving our understanding of how stem cell states influence early hCO cell types may increase reliability of hCO differentiations. Cross-site reproducibility of hCO cell type proportions and organization lays the foundation for future collaborative prospective meta-analytic studies modeling neurodevelopmental disorders in hCOs.

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Section: Organoids Produce Expected Cell Typessupporting

confidence: 59%

Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture

Glass,

Waxman,

Yamashita

et al. 2023

Preprint

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“…These neurons can re-activate their maturational process to finally mature and integrate into adult circuits ( Rotheneichner et al, 2018 ; Benedetti et al, 2020 ). This “neurogenesis without division” can be important for two reasons: first, because they can represent a reservoir of new elements in brain regions that are not endowed with stem/progenitor cells (e.g., the cerebral cortex; Rotheneichner et al, 2018 ; La Rosa et al, 2019 , 2020b ; Coviello et al, 2022 ); second, because it may explain why DCX + cells can be found in non-neurogenic regions, in the absence of cell division. The molecular mechanisms responsible for the stop/re-start of the maturational process, as well as the role they can play once inserted in the circuits, are currently unexplored ( Benedetti and Couillard-Després, 2022 ).…”

Section: Canonical and Non-canonical Neurogenesis: From Neural Stem C...mentioning

confidence: 99%

How Widespread Are the “Young” Neurons of the Mammalian Brain?

Ghibaudi

Bonfanti

2022

Front. Neurosci.

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After the discovery of adult neurogenesis (stem cell-driven production of new neuronal elements), it is conceivable to find young, undifferentiated neurons mixed with mature neurons in the neural networks of the adult mammalian brain. This “canonical” neurogenesis is restricted to small stem cell niches persisting from embryonic germinal layers, yet, the genesis of new neurons has also been reported in various parenchymal brain regions. Whichever the process involved, several populations of “young” neurons can be found at different locations of the brain. Across the years, further complexity emerged: (i) molecules of immaturity can also be expressed by non-dividing cells born during embryogenesis, then maintaining immature features later on; (ii) remarkable interspecies differences exist concerning the types, location, amount of undifferentiated neurons; (iii) re-expression of immaturity can occur in aging (dematuration). These twists are introducing a somewhat different definition of neurogenesis than normally assumed, in which our knowledge of the “young” neurons is less sharp. In this emerging complexity, there is a need for complete mapping of the different “types” of young neurons, considering their role in postnatal development, plasticity, functioning, and interspecies differences. Several important aspects are at stake: the possible role(s) that the young neurons may play in maintaining brain efficiency and in prevention/repair of neurological disorders; nonetheless, the correct translation of results obtained from laboratory rodents. Hence, the open question is: how many types of undifferentiated neurons do exist in the brain, and how widespread are they?

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“…Strong evidence suggests that immature neurons in the amygdala are destined to become excitatory neurons (Sorrells et al, 2019), but it is still largely debated whether immature neurons in layer II of the cerebral cortex are destined to become principal excitatory neurons or inhibitory interneurons (Cai et al, 2009; König et al, 2016; Luzzati et al, 2009; Varea et al, 2011; Xiong et al, 2010; Zhang et al, 2009). Although some discrepancies between studies can be attributed to technical and inter‐species differences, most studies that have tried to decipher the identity and fate of immature neurons in layer II of the cerebral cortex did not necessarily focus on specific cortical regions (Coviello et al, 2022; Luzzati et al, 2009; Varea et al, 2011; Xiong et al, 2008), raising the possibility that region‐specific differences exist.…”

Section: Discussionmentioning

confidence: 99%

Structural plasticity in the entorhinal and perirhinal cortices following hippocampal lesions in rhesus monkeys

Villard,

Chareyron,

Piguet

et al. 2023

Hippocampus

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Immature neurons expressing the Bcl2 protein are present in various regions of the mammalian brain, including the amygdala and the entorhinal and perirhinal cortices. Their functional role is unknown but we have previously shown that neonatal and adult hippocampal lesions increase their differentiation in the monkey amygdala. Here, we assessed whether hippocampal lesions similarly affect immature neurons in the entorhinal and perirhinal cortices. Since Bcl2‐positive cells were found mainly in areas Eo, Er, and Elr of the entorhinal cortex and in layer II of the perirhinal cortex, we also used Nissl‐stained sections to determine the number and soma size of immature and mature neurons in layer III of area Er and layer II of area 36 of the perirhinal cortex. We found different structural changes in these regions following hippocampal lesions, which were influenced by the time of the lesion. In neonate‐lesioned monkeys, the number of immature neurons in the entorhinal and perirhinal cortices was generally higher than in controls. The number of mature neurons was also higher in layer III of area Er of neonate‐lesioned monkeys but no differences were found in layer II of area 36. In adult‐lesioned monkeys, the number of immature neurons in the entorhinal cortex was lower than in controls but did not differ from controls in the perirhinal cortex. The number of mature neurons in layer III of area Er did not differ from controls, but the number of small, mature neurons in layer II of area 36 was lower than in controls. In sum, hippocampal lesions impacted populations of mature and immature neurons in discrete regions and layers of the entorhinal and perirhinal cortices, which are interconnected with the amygdala and provide major cortical inputs to the hippocampus. These structural changes may contribute to some functional recovery following hippocampal injury in an age‐dependent manner.

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Phenotype and Distribution of Immature Neurons in the Human Cerebral Cortex Layer II

Cited by 12 publications

References 59 publications

Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture

Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture

How Widespread Are the “Young” Neurons of the Mammalian Brain?

Structural plasticity in the entorhinal and perirhinal cortices following hippocampal lesions in rhesus monkeys

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