Metabolic regulation of the skeletal stem cell niche

Información del proyecto

MERLIN

Identificador del acuerdo de subvención: 101117555

DOI

10.3030/101117555

Fecha de la firma de la CE 27 Noviembre 2023

Fecha de inicio 1 Enero 2024

Fecha de finalización 31 Diciembre 2028

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 1 499 821,25

Aportación de la UE

€ 1 499 821,00

Coordinado por

Masarykova univerzita
Czechia

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

Período documentado: 2024-01-01 hasta 2026-06-30

Resumen del contexto y de los objetivos generales del proyecto

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

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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.