# Unbiased mapping of skeletal stem cell function at single cell resolution in homeostasis and injury.

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $180,857

## Abstract

Project Summary
Tissue integrity is maintained by specialized adult stem cells that replenish old and damaged cells. During aging
and in disease states, stem cell function is compromised leading to progressive degeneration of the structure
and function of vital organs. This is particularly apparent in the skeleton, which becomes increasingly fragile and
prone to fractures as we age. To uncover and counteract the mechanisms of skeletal degeneration and enhance
bone repair, we must first define skeletal stem and progenitor cell (SSPC) behavior in vivo and determine the
essential regulators of cellular function. This is a technically challenging feat as, in contrast to other organs where
stem cells reside within a defined physical location and are readily identified by gene and protein expression,
cells with progenitor activity can be found throughout bone and there are no specific markers to identify these in
situ. As a result, we still know remarkably little about SSPCs, including whether a multipotent stem cell exists in
vivo or if bone is maintained by a pool of lineage-restricted progenitors. Additionally, it is unclear whether
progenitors from different locations are functionally equivalent. Recently, we identified several distinct skeletal
populations with stem cell characteristics that demonstrate distinct dynamic responses to injury. We hypothesize
that these correspond to SSPC subtypes from different anatomical regions of bone and that they play unique
roles in skeletal regeneration in homeostasis and injury repair. We will leverage cutting-edge technologies to
investigate this hypothesis. In the first part of this proposal, we will perform parallel in vivo clonal functional and
transcriptional analysis to identify cells with progenitor activity in an unbiased manner, interrogate the
differentiation potential of SSPCs in defined bone regions and distinguish gene expression signatures
associated with precise cellular behaviors. These experiments will, for the first time, establish the phenotype
and function of individual SSPCs in their native environment and across distinct local niches, providing a holistic
overview of the SSPC landscape to enable the identification of novel regulators of stem cell activity and markers
to enable the isolation of therapeutically useful cell populations. In the second part of this proposal, we will chart
the dynamic response and contribution of individual progenitors to the repair of various types of bone
injury. These data will reveal the key cell populations driving discrete stages of bone healing and their
transcriptional response to injury, including the signaling pathway signatures enriched in progenitors. Together
this study will dissect the complex web of skeletal stem cell states to facilitate the development of targeted
strategies to improve bone health and fracture healing.

## Key facts

- **NIH application ID:** 10788450
- **Project number:** 5R21AR081268-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Philipp Leucht
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $180,857
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10788450

## Citation

> US National Institutes of Health, RePORTER application 10788450, Unbiased mapping of skeletal stem cell function at single cell resolution in homeostasis and injury. (5R21AR081268-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10788450. Licensed CC0.

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