Dissecting Microglia vulnerability to STress response in Multiple Sclerosis through human iPSC modelling

Description du projet

Les cellules gliales au cœur de la progression de la SEP

La sclérose en plaques (SEP) est généralement étudiée à travers cellules immunitaires qui attaquent le cerveau. Les chercheurs se concentrent à présent sur les cellules gliales. Le projet MiST-MS, financé par le CER, entend déterminer si le vieillissement et les réponses au stress des cellules gliales peuvent être à l’origine d’inflammations et d’incapacités à long terme. Il s’appuiera sur la microglie dérivée de cellules souches humaines et sur le criblage CRISPR pour déterminer les voies moléculaires qui influencent la résilience ou la vulnérabilité de ces cellules. En ce qui concerne les patients, l’objectif du projet est de développer des traitements en comparant les réponses gliales et neuronales chez les personnes souffrant de lésions chroniques actives et chez celles qui n’en souffrent pas. Il entend établir de nouvelles cibles pour les traitements susceptibles de ralentir ou d’arrêter la progression de la SEP.

Objectif

Shifting from the traditional focus on central nervous system-targeting lymphocytes, MiST-MS posits that glial responses, particularly cellular senescence, are required to compartmentalized self-sustaining chronic inflammation in multiple sclerosis (MS) and related long-term clinical outcomes, including disability. MiST-MS is specifically designed to address the urgent need to identify new therapeutic targets to halt MS clinical progression through two interconnected research lines.
The project will first identify cell-specific perturbations and molecular pathways associated with inflammation-driven early brain aging using MS human iPSC-derived microglia and genome-wide CRISPR-Cas9 screenings. By employing cutting-edge computational methodologies (single-cell CRISPR-seq, multi-omics integration, composite assessment, and cellular networking/signaling), MiST-MS offers a unique opportunity to identify and dissect mechanisms underlying microglia resilience versus vulnerability and their impact on stress responses, both independently and within the context of hiPSC-derived inflamed glia-enriched brain organoids. MiST-MS represents a ground-breaking modeling pipeline to study inflammation-driven early brain aging in MS.
At the patient-level, since MS patients with evidence of smoldering inflammation (marked by the presence of chronic active lesions by in vivo MRI) exhibit poor tissue repair capacity and worse clinical outcomes, the project will also aim to identify common and divergent glial and neuronal responses between MS patients with and without chronic active lesions generating human iPSC lines for personalized medicine applications.
In summary, MiST-MS is a highly innovative interdisciplinary project that provides an unprecedented understanding of microglia states in response to injury and streamlines the rational design of future therapies to mitigate chronic inflammation-driven premature brain aging and halt MS clinical progression.