SCIENSC · Identification of Transiently Formed Immune-Endogenous Neural Stem Cell Niches in Spinal Cord Injury
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2023-09-01 → 2025-08-31
- EU contribution
- €222,728
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Identification of Transiently Formed Immune-Endogenous Neural Stem Cell Niches in Spinal Cord Injury
Spinal cord injury (SCI) is a devastating condition of the nervous system, often leading to lifelong paralysis with no effective treatment. After an injury, immune cells rapidly invade the spinal cord, and at the same time a small pool of endogenous neural stem cells (eNSCs) becomes activated. These eNSCs have an intrinsic potential to aid the injured spinal cord repair, but due to the restrictive spinal cord cellular and molecular environment they mostly turn into glial scar-forming cells that in the long run restrict repair. The SCIENSC project was designed to uncover how the immune system communicates with neural stem cells, with the aim of determining if and which immune signals block or promote regeneration and establish new experimental models that allow these interactions to be studied in a reproducible, ethical and high-throughput manner. Three objectives guided the project: 1. Map spatiotemporal immune-cell dynamics after spinal-cord injury and identify cell populations that interact with eNSCs. 2. Characterise molecular communication pathways between immune cells and eNSCs that influence stem cell cellular behaviour. 3. Lay the groundwork for identifying DNA enhancer elements that are specifically activated by injury in key immune cells, paving the way for targeted, tissue and context-dependent therapeutic modulation. The project resulted in generating new biological insights into neuro-immune regulation of repair and also delivered a modular 3D spinal cord injury organoid model that can reduce animal use and accelerate therapeutic discovery. These advances support the EU’s strategic goals in health research, open science, and the 3Rs principle (replacement, reduction and refinement of animal experimentation).
Data: CORDIS, © European Union
Project objective
Despite endogenous neural stem cells (eNSCs) being present in the adult mammalian central nervous system (CNS), their neuronal potential upon injury is rarely achieved in the brain and never in the spinal cord (SC) environment. This makes widespread SC injuries (SCIs) especially challenging to treat. Even though SC eNSCs give rise to astrocytes, oligodendrocytes, and neurons in vitro, they almost exclusively generate glial scar-forming astrocytes, seldom myelinating oligodendrocytes, and never neurons in mammalian models. We still do not know the exact SC niche cues preventing eNSCs from efficiently assuming oligodendrocyte and neuronal fates, averting a functional SC healing. Notably, SCI induces a vast immune response and I hypothesise that immune cells that are responsive to the SCI, contribute to eNSC niche formation, where they can exert an effect on eNSC regulation. I will investigate this by unravelling (O1) temporal, heterogenous immune responses to the SCI and (O2) their spatial interplay with the eNSCs using advanced methodologies, such as spectral flow cytometry and spatial transcriptomics. This will enable me to identify which of these immune cells affect eNSC gene regulatory networks leading to instigation of astrocyte but not oligodendrocyte or neuronal fates. Finally, (O3) I will identify SCI-specific enhancer elements of the immune cells of interest by comparing chromatin signatures of these immune cell types located across different tissues. This knowledge will present a ‘divide and conquer’ opportunity – to compartmentalise and disconnect immune system across different tissues enabling a targeted immune cell manipulation specifically within the SCI environment. The long-term outcome of this project will help the design of enhancer-based immuno-modulatory therapies to dictate eNSC fates and generate oligodendrocytes and neurons in vivo leading to a functional SCI recovery.
Original text from CORDIS.
Participants
- KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
Links
- View on CORDIS
- DOI: 10.3030/101066953
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e50eee7878&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e520311add&appId=PPGMS
Data: CORDIS, © European Union