title: Intrinsic Age-Dependent Changes and Cell-Cell Contacts Regulate Nephron Progenitor Lifespan.
abstract: During fetal development, nephrons of the metanephric kidney form from a mesenchymal progenitor population that differentiates en masse before or shortly after birth. We explored intrinsic and extrinsic mechanisms controlling progenitor lifespan in a transplantation assay that allowed us to compare engraftment of old and young progenitors into the same young niche. The progenitors displayed an age-dependent decrease in proliferation and concomitant increase in niche exit rates. Single-cell transcriptome profiling revealed progressive age-dependent changes, with heterogeneity increasing in older populations. Age-dependent elevation in mTor and reduction in Fgf20 could contribute to increased exit rates. Importantly, 30% of old progenitors remained in the niche for up to 1 week post engraftment, a net gain of 50% to their lifespan, but only if surrounded by young neighbors. We provide evidence in support of a model in which intrinsic age-dependent changes affect inter-progenitor interactions that drive cessation of nephrogenesis.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Brunskill
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
authors.forename: S Steven
authors.initials: SS
authors.lastname: Potter
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Dexheimer
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Salomonis
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Christian I
authors.initials: CI
authors.lastname: Hong
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Tongli
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA. Electronic address: raphael.kopan@cchmc.org.
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D005346:Fibroblast Growth Factors / Q000502:physiology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D007668:Kidney / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008962:Models, Theoretical; D009399:Nephrons / Q000166:cytology* / Q000378:metabolism; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000502:physiology*; D059010:Single-Cell Analysis / Q000379:methods; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C498812:Fgf20 protein, mouse; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Fgf20; aging; kidney; mTor; nephron; stem cells