# Single-cell analysis of the craniofacial skeletal stem cell niche

> **NIH NIH K99** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $103,064

## Abstract

Stem cells reside in specialized niches that support their long-term maintenance. Disruption of the niche, for
example due to aging, injury, or genetic mutations, can lead to declines in stem cells that result in an ability to
maintain and repair tissues. Compared to our understanding of the stem cells that maintain and repair skeletal
tissues, we know much less about the cell types that constitute the niche for skeletal stem cells. In this
proposal, I have taken an innovative single-cell transcriptomic approach to characterize potential niche cells in
the zebrafish face. Preliminary data have uncovered molecular signatures of putative niche cells, including
homologs of genes that when mutated cause craniofacial malformations in humans: WNT5A (Robinow
Syndrome), HGD (Alkaptonuria, aka “black bone disease”), and PAH (maternal Phenylketonuria). This analysis
suggests a role for Wnt5a as a niche-derived paracrine factor for skeletal stem cell maintenance, and an
unexpected local role for phenylalanine catabolism, outside the liver, in protecting craniofacial skeletal tissues.
The aims outlined in this proposal leverage powerful genomic, genetic, and high-resolution imaging
approaches to test that niche cells are located in the outer periosteum in both fish and mammals (Aim 1), that
niche cells and Wnt5a secretion act to maintain skeletal stem cells in the inner periosteum (Aim 2), and that
efficient breakdown of phenylalanine in niche cells is critical for craniofacial skeletal health (Aim 3). Completion
of these aims will inform how defects in the niche result in both developmental defects in the face (such as in
Robinow Syndrome) and a failure to maintain the facial skeleton (such as with the severe arthritis seen in
Alkaptonuria). These findings may also lead to future therapies aimed at better maintaining and repairing the
skeleton through modulating the niche.
The project and mentorship plan outlined in this proposal were designed to lay the groundwork for my career
goal of obtaining a position as a tenure-track Assistant Professor at a top-tier academic research institution.
During the K99 phase, I will receive mentorship in zebrafish biology from Gage Crump and crucial mouse
training from my co-mentor Yang Chai. Regular interactions with clinician-scientists Shoji Yano and Kathryn
Moseley, experts in Phenylketonuria and metabolic diseases and members of my advisory committee, will
allow me to connect findings to human health. Career development activities at USC will prepare me for the
transition to an independent faculty position during the R00 phase. As USC hosts one of the most experienced
communities of craniofacial and skeletal biologists in the country, there are few better places to conduct this
research and acquire the training to achieve my career goals.

## Key facts

- **NIH application ID:** 10173754
- **Project number:** 5K99DE029858-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Peter Fabian
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $103,064
- **Award type:** 5
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173754

## Citation

> US National Institutes of Health, RePORTER application 10173754, Single-cell analysis of the craniofacial skeletal stem cell niche (5K99DE029858-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10173754. Licensed CC0.

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