Neuronal control of fascia

Información del proyecto

NEUROFASCIA

Identificador del acuerdo de subvención: 101088955

DOI

10.3030/101088955

Fecha de la firma de la CE 19 Junio 2023

Fecha de inicio 1 Julio 2023

Fecha de finalización 30 Junio 2028

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 2 000 000,00

Aportación de la UE

€ 2 000 000,00

Coordinado por

TEL AVIV UNIVERSITY
Israel

Periodic Reporting for period 1 - NEUROFASCIA (Neuronal control of fascia)

Período documentado: 2023-07-01 hasta 2025-12-31

Resumen del contexto y de los objetivos generales del proyecto

The NEUROFASCIA project set out to investigate one of the most overlooked tissues of the body: the fascia. Fascia is the connective tissue that envelops muscles, organs, and cavities throughout the body. Traditionally regarded as a passive structural layer, fascia is in fact richly innervated and populated by immune cells. This raised a fundamental question: could fascia act as a sensory and regulatory interface between the brain and the body?
The central objective of the project was to test the hypothesis that fascia is a bidirectional communication hub. On one hand, it can record local tissue conditions and relay this information to the brain through its sensory innervation. On the other, it can receive and integrate autonomic neuronal signals that modulate its immune and structural state.
To address this, the project pursued three major aims:
1. Characterization – mapping fascia’s anatomical organization, neuronal innervation, and resident immune populations using single-cell genomics, histology, and advanced imaging.
2. Function – determining how inflammation in fascia is represented in the brain and how it shapes pain perception and behavior.
3. Modulation – uncovering how neuronal activity and stress affect fascia’s immune and structural composition.
Progress toward these goals required the adaptation of new methodologies, such as fascia fluid proteomics to capture dynamic biochemical signatures, label-free Second Harmonic Generation imaging to visualize collagen architecture, and nanoparticle-based tools for localized manipulation. These approaches enabled insights into fascia’s diversity across anatomical sites and between sexes, showing unexpectedly strong sex-dependent differences in tissue structure, immune composition, and stress responses.
By shifting the perception of fascia from a passive wrapping to an active sensory and immune organ, the project advances our understanding of how the brain integrates body signals to maintain homeostasis. The findings provide a new framework for studying neuro-immune communication, highlighting fascia as a key player in systemic physiology.
The broader impact of NEUROFASCIA lies in creating the conceptual and technical foundations for a field that scarcely existed before. The results redefine fascia as a research frontier in neuroscience and immunology, with potential long-term implications for understanding how the brain interacts with peripheral tissues to regulate health and disease.

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

Progress Summary: Preclinical phase and key discoveries
During the preclinical phase in mice, we uncovered unexpected but significant sex-based differences that have reshaped our research focus. Most notably, we identified a unique subset of immune cells present specifically in the fascia of females - a direction not initially planned but now central to refining our clinical trial framework and objectives. Importantly, this discovery emerged from a systematic comparison between male and female mice, which was integrated into all experimental stages.
In parallel, we are investigating a potentially non-invasive method to detect similar immune-related changes in women. If successful, this approach could broaden the clinical applicability of our findings and enhance the study's translational value.

Activities Performed
• Characterization of fascia: Optimized isolation protocols, antibody panels, and imaging techniques (confocal, SHG). Conducted histology, cytometry, and single-cell RNA-seq to profile fascia from different sites and sexes. Developed fascia fluid proteomics to capture local biochemical signatures.
• Functional studies of fascia inflammation: Established localized inflammation models (LPS, zymosan, nanoparticle-mediated delivery). Began neuronal activity mapping (TRAP mice) and performed nociception assays (Von Frey, hot plate), demonstrating altered pain sensitivity during fascia inflammation.
• Neural regulation of fascia: Investigated stress and depression models (social isolation, corticosterone, noradrenaline), revealing strong sex-specific remodeling of fascia immune and structural states. Performed single-cell transcriptomic analysis of these responses.
• Methodological development: Advanced SHG imaging in collaboration with TAU Nano Center, implemented nanoparticle-based delivery for localized manipulation, and piloted fascia fluid proteomics as a diagnostic-like platform.
• Translational steps: Initiated collaboration with Ichilov Medical Center to obtain ethical approval for fascia sampling from fibromyalgia patients, and in parallel tested patient serum effects on mouse fascia.

Main Achievements:
• Discovery of a female-specific fascia immune population expressing cholinergic enzymes.
• Development of fascia fluid proteomics, providing a novel platform for monitoring local biochemical changes.
• Identification of sex-dependent fascia remodeling in response to stress and depression, highlighting divergent neuro-immune pathways.
• Establishment of collaborations and translational pipelines bridging fundamental fascia research to potential clinical applications.

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)

The NEUROFASCIA project has advanced the field of neuro-immune research by positioning fascia as a previously overlooked but central player in brain–body communication. The results go beyond the state of the art in several ways:
1. Redefining fascia biology: Our work shows that fascia is not a passive wrapping tissue, but a highly diverse organ with site-specific and sex-specific features. These findings establish fascia as a new frontier in systemic physiology and highlight the need to integrate fascia biology into neuroscience and immunology.
2. New methodological platforms: We introduced three technological innovations, fascia fluid proteomics, SHG imaging with biomechanical readouts, and nanoparticle-based manipulation, that together open the possibility of studying fascia in ways that were not previously feasible. These methods may also be adapted by other researchers, amplifying their scientific reach.
3. Unexpected sex-specific pathways: The discovery of female-specific immune subsets and divergent responses to stress and depression highlights sex as a critical biological variable. This is a conceptual breakthrough that impacts both basic research design and the development of future therapies.
4. Translational potential: By preparing for fascia sampling from fibromyalgia patients and developing parallel serum-to-mouse models, we began bridging our fundamental insights to human studies. This provides a translational pipeline that could deliver biomarkers or mechanistic insights into poorly understood conditions.
Future uptake and needs:
• Further research and validation: Larger-scale studies to consolidate findings across different fascia sites, sexes, and models.
• Technology transfer and dissemination: Making protocols for fascia proteomics and imaging available to the community, encouraging broader use and standardization.
• Clinical integration: Collaboration with hospitals to establish ethical frameworks for fascia sampling, coupled with regulatory support for potential diagnostic applications.
In summary, NEUROFASCIA has pushed the boundaries of our understanding of connective tissue biology, establishing fascia as an active sensory and immune organ. These findings expand the frontier and lay foundations for clinical applications, with the potential to impact conditions that currently lack mechanistic explanations.