Intestinal stem cell aging at single-cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics

Jiahn Choi, Michele Houston, Ruixuan Wang, Kenny Ye, Wenge Li, Xusheng Zhang, Derek M. Huffman, Leonard H. Augenlicht

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The intestinal epithelium consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an ordered fashion as the cells progress along the crypt-luminal axis. Perturbed function of Lgr5hi ISCs with aging is documented, but the consequent impact on overall mucosal homeostasis has not been defined. Using single-cell RNA sequencing, the progressive maturation of progeny was dissected in the mouse intestine, which revealed that transcriptional reprogramming with aging in Lgr5hi ISCs retarded the maturation of cells in their progression along the crypt-luminal axis. Importantly, treatment with metformin or rapamycin at a late stage of mouse lifespan reversed the effects of aging on the function of Lgr5hi ISCs and subsequent maturation of progenitors. The effects of metformin and rapamycin overlapped in reversing changes of transcriptional profiles but were also complementary, with metformin more efficient than rapamycin in correcting the developmental trajectory. Therefore, our data identify novel effects of aging on stem cells and the maturation of their daughter cells contributing to the decline of epithelial regeneration and the correction by geroprotectors.

Original languageEnglish (US)
Article numbere13802
JournalAging cell
Volume22
Issue number5
DOIs
StatePublished - May 2023

Keywords

  • gerotherapeutics
  • intestinal stem cell aging
  • intestinal stem cells
  • metformin
  • rapamycin
  • single-cell RNA sequencing

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Fingerprint

Dive into the research topics of 'Intestinal stem cell aging at single-cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics'. Together they form a unique fingerprint.

Cite this