Abstract
The use of differentiating human induced pluripotent stem cells (hiPSCs) in mini-tissue organoids provides an invaluable resource for regenerative medicine applications, particularly in the field of disease modeling. However, most studies using a kidney organoid model, focused solely on the transcriptomics and did not explore mechanisms of regulating kidney organoids related to metabolic effects and maturational phenotype. Here, we applied metabolomics coupled with transcriptomics to investigate the metabolic dynamics and function during kidney organoid differentiation. Not only did we validate the dominant metabolic alteration from glycolysis to oxidative phosphorylation in the iPSC differentiation process but we also showed that glycine, serine, and threonine metabolism had a regulatory role during kidney organoid formation and lineage maturation. Notably, serine had a role in regulating S-adenosylmethionine (SAM) to facilitate kidney organoid formation by altering DNA methylation. Our data revealed that analysis of metabolic characterization broadens our ability to understand phenotype regulation. The utilization of this comparative omics approach, in studying kidney organoid formation, can aid in deciphering unique knowledge about the biological and physiological processes involved in organoid-based disease modeling or drug screening.
Highlights
Personalized induced pluripotent stem cells is an emerging technology that increases the number of options available for regenerative medicine applications (Robinton and Daley, 2012; Cossu et al, 2018)
The formed embryoid bodies (EBs) were cultured in “Stage II” medium from day 3 (D3) until tubule formation which was visible under bright-field microscopy after day 8 (D8), and tubule structuralized organoids at around day 14 (D14) (Figures 1D– F)
We investigated the metabolic dynamics during kidney organoid differentiation for 14 days, and we used untargeted metabolomics coupled with transcriptomics to determine the global portrait of the metabolic features (Figure 6)
Summary
Personalized induced pluripotent stem cells (iPSCs) is an emerging technology that increases the number of options available for regenerative medicine applications (Robinton and Daley, 2012; Cossu et al, 2018). Generating complex kidney tissues, such as kidney organoids, in a large quantity from personalized human induced pluripotent stem cells (hiPSCs) have broadened our ability to study human kidney development, disease, and even perform tissue engineering (Xia et al, 2013; Taguchi et al, 2014; Takasato et al, 2014, 2015; Freedman et al, 2015; Morizane et al, 2015; Taguchi and Nishinakamura, 2017; Przepiorski et al, 2018; Low et al, 2019). Batch variation was not accounted for, and during the culture process, quality feedback from the derived kidney organoids was not performed adequately
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