Metabolic regulation of the skeletal stem cell niche

Introduction

The continued health of many of our organs, including the skeleton, relies on the function of specialized stem cells. These stem cells reside in niches that support their long-term maintenance. Disruption of the niche due to aging, injury, or genetic mutations can lead to declines in stem cells and a failure to maintain and repair tissues.

Current Understanding

Compared to our understanding of the stem cells that maintain and repair our skeleton, we know much less about the cell types that constitute their niche. My prior large-scale genomics studies have uncovered a novel niche cell type for the skeleton.

Metabolic Profile

Intriguingly, these niche cells are defined by a unique metabolic profile, highlighting in particular enzymes for Phenylalanine (Phe) / Tyrosine (Tyr) metabolism and glycogen synthesis. Traditionally, it has been thought that Phe/Tyr are degraded primarily in the liver.

Clinical Implications

The skeletal malformations in patients with:

1. Phenylketonuria (mutation in PAH)
2. Tyrosinemia (I-III, mutations in FAH, TAT, HPD)
3. Alkaptonuria, a.k.a. "black bone disease" (mutation in HGD)

have been interpreted as the results of systemic intoxication by accumulated metabolites. My dogma-shattering result suggests that local regulation of Phe/Tyr degradation might be a critical strategy to support the skeleton.

Research Objectives

I will establish a research group that leverages the powerful genomic, genetic, and high-resolution imaging strengths of zebrafish to test the requirements of niche cells in skeletal stem cell homeostasis and the roles of metabolism in stem cell maintenance.

Future Implications

Findings from my proposed studies will inform future therapies aimed at correcting metabolic diseases and restoring stem cell function and skeletal health by modulating the niche.