Intrinsic Age-Dependent Changes and Cell-Cell Contacts Regulate Nephron Progenitor Lifespan

Dev Cell. 2015 Oct 12;35(1):49-62. doi: 10.1016/j.devcel.2015.09.009.

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.

Keywords: Fgf20; aging; kidney; mTor; nephron; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Communication*
  • Cell Differentiation*
  • Cell Proliferation
  • Cellular Senescence*
  • Fibroblast Growth Factors / physiology
  • High-Throughput Nucleotide Sequencing / methods
  • Kidney / cytology*
  • Kidney / metabolism
  • Mice
  • Mice, Knockout
  • Models, Theoretical
  • Nephrons / cytology*
  • Nephrons / metabolism
  • Organ Culture Techniques
  • Organogenesis / physiology*
  • Single-Cell Analysis / methods
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism

Substances

  • Biomarkers
  • Fgf20 protein, mouse
  • Wnt Proteins
  • Fibroblast Growth Factors
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse

Associated data

  • GEO/GSE66202