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The centrosomal protein 83 (CEP83) regulates human pluripotent stem cell differentiation towards the kidney lineage

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Title:The centrosomal protein 83 (CEP83) regulates human pluripotent stem cell differentiation towards the kidney lineage
Creators Name:Mansour, F. and Hinze, C. and Telugu, N.S. and Kresoja, J. and Shaheed, I.B. and Mosimann, C. and Diecke, S. and Schmidt-Ott, K.M.
Abstract:During embryonic development, the mesoderm undergoes patterning into diverse lineages including axial, paraxial, and lateral plate mesoderm (LPM). Within the LPM, the so-called intermediate mesoderm (IM) forms kidney and urogenital tract progenitor cells, while the remaining LPM forms cardiovascular, hematopoietic, mesothelial, and additional progenitor cells. The signals that regulate these early lineage decisions are incompletely understood. Here, we found that the centrosomal protein 83 (CEP83), a centriolar component necessary for primary cilia formation and mutated in pediatric kidney disease, influences the differentiation of human induced pluripotent stem cells (hiPSCs) towards intermediate mesoderm. We induced inactivating deletions of (CEP83) in hiPSCs and applied a 7 day in vitro protocol of intermediate mesoderm kidney progenitor differentiation, based on timed application of WNT and FGF agonists. We characterized induced mesodermal cell populations using single cell and bulk transcriptomics and tested their ability to form kidney structures in subsequent organoid culture. While hiPSCs with homozygous (CEP83) inactivation were normal regarding morphology and transcriptome, their induced differentiation into IM progenitor cells was perturbed. Mesodermal cells induced after 7 days of monolayer culture of (CEP83)-deficient hiPCS exhibited absent or elongated primary cilia, displayed decreased expression of critical IM genes ((PAX8), (EYA1), (HOXB7)), and an aberrant induction of LPM markers (e. g. (FOXF1), (FOXF2), (FENDRR), (HAND1) ,(HAND2)). Upon subsequent organoid culture, wildtype cells differentiated to form kidney tubules and glomerular-like structures, whereas (CEP83)-deficient cells failed to generate kidney cell types, instead upregulating cardiomyocyte, vascular, and more general LPM progenitor markers. Our data suggest that (CEP83) regulates the balance of intermediate mesoderm and lateral plate mesoderm formation from human pluripotent stem cells, identifying a potential link between centriolar or ciliary function and mesodermal lineage induction.
Keywords:Distal Appendages, Centrosomal Protein, Kidney Development, Pluripotent Stem Cells, Kidney Organoids, Primary Cilium, CRISPR-Cas
Publisher:eLife Sciences Publications
Page Range:e80165
Date:12 October 2022
Official Publication:https://doi.org/10.7554/elife.80165
PubMed:View item in PubMed

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