Spatial dynamic metabolomics identifies metabolic trajectories during human kidney epithelium development

Accumulating evidence demonstrates important roles for metabolism in cell fate determination. However, It is a challenge to assess metabolism at a spatial resolution that acknowledges both heterogeneity and cellular dynamics in its tissue microenvironment. Using a multi-omics platform to study cell-type specific dynamics in metabolism in complex tissues, we describe the metabolic trajectories during nephrogenesis in the developing human kidney. Exploiting <em>in situ </em>analysis of isotopic labeling, a shift from glycolysis towards fatty acid β-oxidation was observed during the differentiation from the renal vesicle, towards the S-shaped body and the proximal tubules. In addition, we show that hiPSC-derived kidney organoids are characterized by a metabolic immature phenotype, that fails to use mitochondrial long-chain fatty acids for energy metabolism. Furthermore, supplementation of butyrate enhances tubular epithelial differentiation and maturation in cultured kidney organoids. Our findings highlight the relevance of understanding metabolic trajectories to efficiently guide stem cell differentiation.