# Cell Fate Decisions in Epithelial Stem Cell Lineages

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $511,178

## Abstract

Abstract
My lab is broadly interested in understanding how cellular differentiation is controlled within a continuously
renewing epithelial tissue. Conserved features of these tissues that are not fully understood and unify studies
across experimental systems include a flexible niche structure, a “transit amplification” stage which typically has
significant cellular plasticity, and the ability of neighboring stem cell lineages to compete for niche occupancy.
To understand these emergent properties of tissues, we have focused on approaches that allow for the study of
cell behaviors within the native, in vivo context in at cellular resolution. Our primary model system is the follicle
epithelium of the Drosophila ovary, and we have recently extended our studies into the mouse intestinal
epithelium. Our contributions over the past ten years include identifying the source and identity of the follicle
stem cell (FSC) niche ligands, defining a self-renewal network for FSCs, describing new mechanisms that
promote the segregation of stem cell and daughter cell fates, and the establishment and use of the FSC lineage
as a model for understanding stem cell niche competition. Our current studies are investigating three
interconnected areas. First, we created a cell atlas of the Drosophila ovary that describes the identity, position,
and gene expression profile of over a dozen known and novel cell types. This project has provided useful new
tools that are allowing us to investigate the lineage plasticity of cells in the tissue and has led, for example, to
the discovery that niche cells can convert to stem cells during physiological stress. In addition, these tools provide
us with a new opportunity to study how a dynamic population of niche cells is able to maintain a stable pool of
FSCs amid changing tissue demands. Second, we are investigating the molecular mechanisms that govern
stem cell niche competition. We have identified a broad class of alleles that cause hypercompetition for the niche,
and we are using genetics, quantitative imaging, and mathematical modeling to understand the basis for
selection of one lineage over another. We have also extended these studies into the mouse intestinal epithelium
and found that the process is at least partially conserved. Third, we are investigating the role of intracellular pH
(pHi) in regulating cell fate decisions. We demonstrated that pHi increases during differentiation in both the FSC
lineage and mouse embryonic stem cells, and that this increase in pHi is necessary for differentiation. In
unpublished studies, we discovered a similar requirement for increased pHi in the mouse intestinal stem cell
lineage. Currently, we are focused on understanding how pHi regulates cell fate, with an emphasis on candidate
“pH sensor” proteins, such as β-catenin, that have a pKa within the physiological range. For these proteins, the
gain or loss of a proton functions like a post-translational modification, thus linking pH dynami...

## Key facts

- **NIH application ID:** 10168579
- **Project number:** 5R35GM136348-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Todd Nystul
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $511,178
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168579

## Citation

> US National Institutes of Health, RePORTER application 10168579, Cell Fate Decisions in Epithelial Stem Cell Lineages (5R35GM136348-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168579. Licensed CC0.

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