Spatial dynamic metabolomics identifies metabolic cell fate trajectories in human kidney differentiation

Wang, G.Q.; Heijs, B.; Kostidis, S.; Rietjens, R.G.J.; Koning, M.; Yuan, L.S.; Tiemeier, G.L.; Mahfouz, A.; Dumas, S.J.; Giera, M.; Kers, J.; Lopes, S.M.C.D.; Berg, C.W.V.; Berg, B.M.V.; Rabelink, T.J.

doi:doi:10.1016/j.stem.2022.10.008

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 devel-oping human kidney. Exploiting in situ analysis of isotopic labeling, a shift from glycolysis toward fatty acid b-oxidation was observed during the differentiation from the renal vesicle toward 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. Further-more, supplementation of butyrate enhances tubular epithelial differentiation and maturation in cultured kid-ney organoids. Our...Show moreAccumulating 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 devel-oping human kidney. Exploiting in situ analysis of isotopic labeling, a shift from glycolysis toward fatty acid b-oxidation was observed during the differentiation from the renal vesicle toward 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. Further-more, supplementation of butyrate enhances tubular epithelial differentiation and maturation in cultured kid-ney organoids. Our findings highlight the relevance of understanding metabolic trajectories to efficiently guide stem cell differentiation.Show less

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Spatial dynamic metabolomics identifies metabolic cell fate trajectories in human kidney differentiation