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Village In a Dish: A Model System for Population-scale hiPSC Studies [scRNA-Seq]

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 under different conditions. Human induced pluripotent stem cells (hiPSCs) are uniquely suited to study these context-dependent effects, but to do so requires cell lines from hundreds or thousands of individuals. Village cultures, where multiple hiPSC lines are cultured and differentiated in a single dish, provide an elegant solution for scaling hiPSC 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 back to a donor line using single-cell sequencing and addressing whether line-specific signalling alters the transcriptional profiles of companion lines in a village. We generated single-cell RNA sequence data from hiPSC lines cultured independently (uni-culture) and in villages at three independent sites. Using a mixed linear model framework, we estimate that the proportion of transcriptional variation across cells is predominantly due to donor effects, with minimal evidence of variation due to culturing in a village system. We demonstrate that the genetic, epigenetic or hiPSC line-specific effects explain a large percentage of gene expression variation for many genes, not the village status. This is reiterated by replication of previously identified genetic effects. Finally, we demonstrate consistency in the landscape of cell states between uni- and village-culture systems. We demonstrate that village methods can effectively detect hiPSC line-specific effects, including sensitive dynamics of cell states.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225278 | GEO | 2023/02/14

REPOSITORIES: GEO

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Project description:Renewable in vitro cell cultures, such as lymphoblastoid cell lines (LCLs), have facilitated studies that contributed to our understanding of genetic influence on human traits. However, the degree to which cell lines faithfully maintain differences in donor-specific phenotypes is still debated. We have previously reported that standard cell line maintenance practice results in a loss of donor-specific gene expression signatures in LCLs. An alternative to the LCL model is the induced pluripotent stem cell (iPSC) system, which carries the potential to model tissue-specific physiology through the use of differentiation protocols. Still, existing LCL banks represent an important source of starting material for iPSC generation, and it is possible that the disruptions in gene regulation associated with long-term LCL maintenance could persist through the reprogramming process. To address this concern, we studied the effect of reprogramming mature LCLs to iPSCs on the ensuing gene expression patterns within and between six unrelated donor individuals. We show that the reprogramming process results in a recovery of donor-specific gene regulatory signatures. Since environmental contributions are unlikely to be a source of individual variation in our system of highly passaged cultured cell lines, our observations suggest that the effect of genotype on gene regulation is more pronounced in the iPSCs than in the LCL precursors. Our observations indicate that iPSCs can be a powerful model system for studies of phenotypic variation across individuals in general, and the genetic association with variation in gene regulation in particular. We further conclude that LCLs are an appropriate starting material for iPSC generation. Whole genome gene expression data was collected for 34 samples including 17 iPSC lines and 17 LCL lines on the Illumina HT-12 v4 Expression BeadChip array platform. Three biological replicates of each individual were included in the study, except for one individual for which only two replicates were obtained.

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Village In a Dish: A Model System for Population-scale hiPSC Studies [scRNA-Seq]

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