# Mechanisms driving stem cell responses to injury in planarians

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $53,887

## 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 proliferation
and 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 of
tissue. These pluripotent stem cells can be readily identified, monitored, purified, and thoroughly profiled at the
molecular 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 mitogen-
activated protein kinase (MAPK) pathway is a central driver of these behaviors. MAPK promotes stem cell
differentiation in cultured stem cells, but its roles in physiologically-relevant contexts are 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 stem cells after radiation. We will examine DNA repair and test the
function of conserved genes that are upregulated after 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, and then testing their function in organ regeneration. 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:** 11034451
- **Project number:** 3R01GM139933-04S1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Carolyn Elizabeth Adler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,887
- **Award type:** 3
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11034451

## Citation

> US National Institutes of Health, RePORTER application 11034451, Mechanisms driving stem cell responses to injury in planarians (3R01GM139933-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11034451. Licensed CC0.

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