# The roles of regional specialization, mechanical forces and epigenetic memory after perturbation and injury of the intestinal stem cell microenvironment

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $87,216

## Abstract

PROJECT SUMMARY/ABSTRACT
The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian
tissues. Understanding the intestinal stem cells (ISCs) that fuel this renewal is both an important basic science
question and an essential starting point for translational approaches in regenerative medicine. Genetic
inducible fate mapping (GIFM) studies have identified two principal epithelial stem cell pools in the intestine.
One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the
crypt base, and the other consists of cells expressing Bmi1 or other markers that largely reside above the crypt
base. We have recently demonstrated (Tian et al, Nature, 2011) that Bmi1-expressing ISCs give rise to Lgr5-
expressing ISCs under normal physiological conditions. Importantly, when we specifically ablated Lgr5-
expressing ISCs, Bmi1-expressing ISCs were able to maintain epithelial homeostasis in the proximal small
intestine. These results, which have been confirmed by several other groups, indicated that Lgr5- and Bmi1-
expressing ISCs constitute two distinct, although possibly partially overlapping, populations. An important
question is which signaling pathways regulate these different stem cell populations, and a growing body of
evidence indicates that Wnt and Notch signaling guide both Lgr5- and Bmi1-expressing stem cell self-renewal.
In this application, we propose to employ pathway-specific blocking antibodies to understand the differential
and combinatorial effects of Wnt and Notch signaling on self-renewal and lineage fate decisions in ISCs. This
unique approach – combining antibody blockade and genetic fate mapping – opens up interesting new
avenues beyond the traditional purely genetic approaches. The results of these studies will shed important light
on the mechanisms by which ISCs self-renew and differentiate, which will help to understand the roles of these
ISCs in homeostasis and disease and will help to lay the groundwork for future attempts at organ regeneration.

## Key facts

- **NIH application ID:** 10173172
- **Project number:** 3U01DK103147-07S2
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ophir D Klein
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $87,216
- **Award type:** 3
- **Project period:** 2014-09-05 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173172

## Citation

> US National Institutes of Health, RePORTER application 10173172, The roles of regional specialization, mechanical forces and epigenetic memory after perturbation and injury of the intestinal stem cell microenvironment (3U01DK103147-07S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10173172. Licensed CC0.

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