Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 219, Issue 11, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20212405
Keywords
-
Categories
Funding
- State Research Agency from the Spanish Ministry of Science and Innovation [SAF2016-76598-R, SAF2017-92733-EXP, RTI2018-094834-B-I00, RED2018-102723-T]
- European Regional Development Fund
- Asociacion Espanola Contra el Cancer [PRYGN211184DJOU, PRDMA21370SANT]
- Asociacion Espanola Contra el Cancer (Madrid)
- Comunidad de Madrid
- Health Institute Carlos III (ISCIII)
- Spanish Ministry of Science and Innovation
Ask authors/readers for more resources
This study reveals the important role of transit-amplifying cells in controlling inflammatory signals and R-spondin production, which are essential for maintaining intestinal stem cell proliferation and tissue regeneration.
Intestinal epithelium regenerates rapidly through proliferation of intestinal stem cells (ISCs), orchestrated by potent mitogens secreted within the crypt niche. However, mechanisms regulating these mitogenic factors remain largely unknown. Here, we demonstrate that transit-amplifying (TA) cells, marked by unconventional prefoldin RPB5 interactor (URI), control R-spondin production to guide ISC proliferation. Genetic intestinal URI ablation in mice injures TA cells, reducing their survival capacity, leading to an inflamed tissue and subsequently decreasing R-spondin levels, thereby causing ISC quiescence and disruption of intestinal structure. R-spondin supplementation or restoration of R-spondin levels via cell death inhibition by c-MYC elimination or the suppression of inflammation reinstates ISC proliferation in URI-depleted mice. However, selective c-MYC and p53 suppression are required to fully restore TA cell survival and differentiation capacity and preserve complete intestinal architecture. Our data reveal an unexpected role of TA cells, which represent a signaling platform instrumental for controlling inflammatory cues and R-spondin production, essential for maintaining ISC proliferation and tissue regeneration.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available