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A quantitative framework to evaluate modeling of cortical development by neural stem cells

ABSTRACT: In vitro neural stem cell models are widely used to model a wide range of neuropsychiatric conditions. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease. In this GEO submission, we upload data from 5 lines of phNPCs as well as hiPSCs cultured in two different laboratories all at multiple differentiation time points.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57595 | GEO | 2014/06/01

SECONDARY ACCESSION(S): PRJNA246751

REPOSITORIES: GEO

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Project description:In vitro neural stem cell models are widely used to model a wide range of neuropsychiatric conditions. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease. In this GEO submission, we upload data from 5 lines of phNPCs as well as hiPSCs cultured in two different laboratories all at multiple differentiation time points. phNPCs: For each of 5 lines generated from 3 donors (15-16 PCW), two independent differentiation experiments each containing two replicates were performed and harvested at four time points (1, 4, 8, 12 wks PD; ~16 samples per line; 77 total samples). We confirmed RNA integrity by RIN score with the Agilent 2100 Bioanalyzer (mean +/- sd: 9.16 +/- 0.78). iPSC: Two hiPSC datasets were RNA profiled as part of this study. hiPSCs grown in the Kosik lab was derived from two independent, non-isogenic IPS lines: one derived from a patient carrying a mutant Tau variant G55R and one reference control. For each of these lines, two samples were harvested at each of 0, 1, 4, and 8 weeks PD (total n=16 samples). hiPSCs grown in the Gage lab were from six samples derived from 3 control lines at each of two time points (0 and 4 wk PD, total n=12 samples). Samples were randomized to microarray chip by all biological variables of interest (donor, line, passage, replicate number, differentiation week, plate date, and RIN) to control for potential batch effects.

Project description:Background: Sleeping sickness is caused by the extracellular parasite Trypanosoma brucei and is associated with neuroinflammation and neuropsychiatric disorders, including disruption of sleep/wake patterns, and is now recognised as a circadian disorder. Sleeping sickness is traditionally studied using murine models of infection due to the lack of alternative in vitro systems that fully recapitulate the cellular diversity and functionality of the human brain. The aim of this study is to develop a much-needed in vitro system that reduces and replaces live animals for the study of infections in the central nervous system, using sleeping sickness as a model infection. Methods: We developed a co-culture system using induced pluripotent stem cell (iPSC)-derived cortical human brain organoids and the human pathogen T. b. gambiense to model host-pathogen interactions in vitro. Upon co-culture, we analysed the transcriptional responses of the brain organoids to T. b. gambiense over two time points. Results: We detected broad transcriptional changes in brain organoids exposed to T. b. gambiense, mainly associated with innate immune responses, chemotaxis, and blood vessel differentiation compared to untreated organoids. Conclusions: Our co-culture system provides novel, more ethical avenues to study host-pathogen interactions in the brain as alternative models to experimental infections in mice. Although our data support the use of brain organoids to model host-pathogen interactions during T. brucei infection as an alternative to in vivo models, future work is required to increase the complexity of the organoids ( e.g., addition of microglia and vasculature). We envision that the adoption of organoid systems is beneficial to researchers studying mechanisms of brain infection by protozoan parasites. Furthermore, organoid systems have the potential to be used to study other parasites that affect the brain significantly reducing the number of animals undergoing moderate and/or severe protocols associated with the study of neuroinflammation and brain infections.

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A quantitative framework to evaluate modeling of cortical development by neural stem cells

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