Reduced adhesion of aged intestinal stem cells contributes to an accelerated clonal drift

  • Ali Hageb
  • Torsten Thalheim
  • Kalpana J Nattamai
  • Bettina Möhrle
  • Mehmet Saçma
  • Vadim Sakk
  • Lars Thielecke
  • Cornils Kerstin
  • Carolin Grandy
  • Fabian Port
  • Kay-E Gottschalk
  • Jan-Philipp Mallm
  • Ingmar Glauche
  • Jörg Galle
  • Medhanie A Mulaw
  • Hartmut Geiger

Abstract

Upon aging, the function of the intestinal epithelium declines with a concomitant increase in aging-related diseases. ISCs play an important role in this process. It is known that ISC clonal dynamics follow a neutral drift model. However, it is not clear whether the drift model is still valid in aged ISCs. Tracking of clonal dynamics by clonal tracing revealed that aged crypts drift into monoclonality substantially faster than young ones. However, ISC tracing experiments, in vivo and ex vivo, implied a similar clonal expansion ability of both young and aged ISCs. Single-cell RNA sequencing for 1,920 high Lgr5 ISCs from young and aged mice revealed increased heterogeneity among subgroups of aged ISCs. Genes associated with cell adhesion were down-regulated in aged ISCs. ISCs of aged mice indeed show weaker adhesion to the matrix. Simulations applying a single cell-based model of the small intestinal crypt demonstrated an accelerated clonal drift at reduced adhesion strength, implying a central role for reduced adhesion for affecting clonal dynamics upon aging.

Bibliographical data

Original languageEnglish
Article numbere202201408
ISSN2575-1077
DOIs
Publication statusPublished - 08.2022

Comment Deanary

© 2022 Hageb et al.

PubMed 35487692