Metabolic regulation of the skeletal stem cell niche

Project Information

MERLIN

Grant agreement ID: 101117555

DOI

10.3030/101117555

EC signature date 27 November 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 499 821,25

EU contribution

€ 1 499 821,00

Coordinated by

Masarykova univerzita
Czechia

Periodic Reporting for period 1 - MERLIN (Metabolic regulation of the skeletal stem cell niche)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

Context and Motivation
The long-term health and repair of the skeleton depend on specialized Skeletal Stem Cells (SSCs) and the protective "niches" that maintain them. While SSCs are well-studied, the specific cell types constituting their niche remain poorly understood. Disruption of these niches—whether by aging, injury, or genetic mutations—leads to a failure in tissue maintenance. This project addresses a critical gap: identifying how local niche cells regulate skeletal health and why certain metabolic genetic disorders, such as Alkaptonuria (AKU) and Phenylketonuria (PKU), specifically damage the skeleton.

Overall Objectives
Using the zebrafish as a highly regenerative model, this project aims to: Characterize a Novel Niche Cell Type: Leverage single-cell genomics to investigate a newly discovered niche cell that expresses disease-relevant genes like HGD and PAH. Test SSC Maintenance: Determine if these niche cells are essential for the survival and function of Skeletal Stem Cells. Decipher Local Metabolism: Investigate if Phenylalanine (Phe) and Tyrosine (Tyr) metabolism occurs locally within the skeletal niche—rather than exclusively in the liver—and if defects in this local pathway drive skeletal decay. Validate Disease Phenotypes: Confirm that hgd mutations lead to homogentisate accumulation and structural failure, such as the loss of skeletal adipocytes.

Expected Impact
This research challenges the traditional view that metabolic bone diseases are purely systemic issues. By demonstrating that local dermal fibroblast metabolism can drive focal skeletal pathology, we shift the focus toward the "micro-environment" of the bone. Scientific Innovation: Establishing the role of local Phe/Tyr metabolism provides a new framework for understanding developmental facial defects and degenerative "black bone disease".Therapeutic Potential: Our findings suggest that modulating the niche and its secreted factors—or using pharmacological interventions like NTBC to reverse local metabolic accumulation—could lead to future therapies aimed at restoring skeletal integrity

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

1. Establishment of genetically accessible dermal fibroblast niche population at the skin–skeletal interface.
2. Functional demonstration that niche cell ablation disrupts skeletal maintenance and regeneration.
3. Generation of a zebrafish hgd mutant that recapitulates skeletal ochronosis.
4. Demonstration of local homogentisate deposition in bone using Raman spectroscopy.
5. Pharmacological rescue of skeletal metabolite accumulation with nitisinone.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Alkaptonuria "Black Bone" Paradox: For decades, the field has been stalled by the fact that Hgd mouse models fail to develop the "black bone" phenotype or significant skeletal degeneration seen in humans. We have achieved a major breakthrough by establishing the first high-fidelity animal model for Alkaptonuria. Our zebrafish hgd mutants exhibit definitive homogentisate-specific pigment deposition and structural remodeling, validated by Raman spectroscopy. This provides the community with a robust in vivo platform to study disease etiology and test targeted therapies.
Shifting the Metabolic Paradigm: We have advanced the field beyond the "liver-centric" view of systemic metabolism. Our discovery of a local metabolic module within dermal fibroblasts at the skin-skeletal interface represents a paradigm shift. We have demonstrated that these niche cells act as local metabolic gatekeepers, directly protecting skeletal integrity. This discovery redefines how we approach metabolic bone diseases, moving from systemic treatment strategies toward niche-specific interventions.