# Cell Fate Decisions in Epithelial Stem Cell Lineages

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $44,981

## Abstract

R35 GRANT 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...

## Key facts

- **NIH application ID:** 10226749
- **Project number:** 3R35GM136348-01S1
- **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:** $44,981
- **Award type:** 3
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226749

## Citation

> US National Institutes of Health, RePORTER application 10226749, Cell Fate Decisions in Epithelial Stem Cell Lineages (3R35GM136348-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226749. Licensed CC0.

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