Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells.


Journal Article

Intestinal epithelial stem cells (IESCs) are critical to maintain intestinal epithelial function and homeostasis. We tested the hypothesis that aging promotes IESC dysfunction using old (18-22 months) and young (2-4 month) Sox9-EGFP IESC reporter mice. Different levels of Sox9-EGFP permit analyses of active IESC (Sox9-EGFPLow), activatable reserve IESC and enteroendocrine cells (Sox9-EGFPHigh), Sox9-EGFPSublow progenitors, and Sox9-EGFPNegative differentiated lineages. Crypt-villus morphology, cellular composition and apoptosis were measured by histology. IESC function was assessed by crypt culture, and proliferation by flow cytometry and histology. Main findings were confirmed in Lgr5-EGFP and Lgr5-LacZ mice. Aging-associated gene expression changes were analyzed by Fluidigm mRNA profiling. Crypts culture from old mice yielded fewer and less complex enteroids. Histology revealed increased villus height and Paneth cells per crypt in old mice. Old mice showed increased numbers and hyperproliferation of Sox9-EGFPLow IESC and Sox9-EGFPHigh cells. Cleaved caspase-3 staining demonstrated increased apoptotic cells in crypts and villi of old mice. Gene expression profiling revealed aging-associated changes in mRNAs associated with cell cycle, oxidative stress and apoptosis specifically in IESC. These findings provide new, direct evidence for aging associated IESC dysfunction, and define potential biomarkers and targets for translational studies to assess and maintain IESC function during aging.

Full Text

Duke Authors

Cited Authors

  • Moorefield, EC; Andres, SF; Blue, RE; Van Landeghem, L; Mah, AT; Santoro, MA; Ding, S

Published Date

  • August 2017

Published In

Volume / Issue

  • 9 / 8

Start / End Page

  • 1898 - 1915

PubMed ID

  • 28854151

Pubmed Central ID

  • 28854151

Electronic International Standard Serial Number (EISSN)

  • 1945-4589

International Standard Serial Number (ISSN)

  • 1945-4589

Digital Object Identifier (DOI)

  • 10.18632/aging.101279


  • eng