# Mechanisms driving stem cell responses to injury in planarians

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $91,100

## Abstract

Abstract
Successful regeneration of tissues requires transient increases in stem cell plasticity, proliferation, and
differentiation, in order to produce new cells that integrate with preexisting tissues and organs. Pathways
governing these critical behaviors have been identified, but how injury signals can trigger stem cell
proliferationand differentiation of cells necessary for regeneration remains poorly understood. In most
model organisms, regenerative capacity is limited and stem cells are scarce, which has made it difficult to
pinpoint the mechanisms regulating stem cell proliferation and differentiation after injury. By contrast, the
planarian flatworm Schmidtea mediterranea has abundant stem cells that are activated by injury and fuel
continuous regeneration. Like embryonic stem cells, planarian stem cells have the capacity to differentiate
into any type oftissue. These pluripotent stem cells can be readily identified, monitored, purified, and
thoroughly profiled at themolecular level. We recently made two important discoveries that form the
foundation of this proposal. First, injury of any type appears to protect stem cells from lethal radiation,
because it halts the cell cycle and fewer stem cells undergo apoptosis. Second, we pioneered a chemical
method to selectively remove a single organ,the pharynx. Pharynx regeneration requires the upregulation
of the conserved Forkhead transcription factor FoxA in a discrete subset of stem cells immediately after
this targeted injury. We find that the extracellular signal-regulated kinase (ERK) is a central driver of these
behaviors. ERK promotes differentiation in cultured stem cells, but how it is activated after injury is poorly
understood. Together, these findings establish our central hypothesis, which is that injury synchronizes
the cell cycle, enabling local cues to channel stem cell differentiation toward discrete cell fates. In Aim 1,
we will determine how injury induces cell cycle arrest in stemcells after radiation. We will examine DNA
repair and test the function of conserved genes that are upregulatedafter injury. In Aim 2, we will dissect
the mechanisms driving organ-specific regeneration by purification and single-cell sequencing of stem
cells proliferating after organ loss. We will identify receptors enriched on these cells, and test their function
in organ regeneration to determine if they act upstream of FoxA. In Aim 3, we will identify the upstream
receptors that activate MAP kinase signaling in stem cells with combinations of RNAi, pharmacology and
biochemistry. This proposal exploits our ability to challenge stem cells with precise insults, providing a
lens into the mechanisms that enable flexible stem cell responses during injury and homeostasis.
Understanding the molecular mechanisms that govern stem cell behavior in a physiologically-relevant
context will inform the design of future strategies for regenerative medicine technologies.

## Key facts

- **NIH application ID:** 10387688
- **Project number:** 3R01GM139933-02S1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Carolyn Elizabeth Adler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $91,100
- **Award type:** 3
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387688

## Citation

> US National Institutes of Health, RePORTER application 10387688, Mechanisms driving stem cell responses to injury in planarians (3R01GM139933-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10387688. Licensed CC0.

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