Developing advanced human stem cell models to recapitulate neuron-glia interactions in chronic CNS inflammation
Summary
Multiple Sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease of the central nervous system (CNS) that causes sensory, motor, and cognitive impairment.
Currently, there is no cure for MS, especially in its secondary progressive (SP) stage. Although perturbed interactions between neurons and immune cells are a known hallmark of MS, their specific causes remain poorly understood, hindering the development of effective therapies.
A major barrier to progress is the limitation of existing models. Post-mortem human brain tissue, while histologically relevant, is constrained by high variability and its static, end-stage nature, which prevents the investigation of dynamic disease mechanisms.
To overcome this, this project will develop a cutting-edge, three-dimensional (3D) human brain co-culture system. A human iPSC-based 3D model offers a superior platform that more accurately captures human-specific neuroinflammatory and demyelinating pathology, allowing for precise control over cellular and microenvironmental factors to enable targeted mechanistic studies.
Project aims
- Generate region-specific brain organoids from human iPSCs that recapitulate the neuronal activation deficits seen in MS patients and mouse models of disease.
- Perform comparative profiling of the 3D organoids and post-mortem MS patient brain tissue to validate the conservation of disease-relevant signatures.
- Leverage the validated 3D organoid platform to mechanistically elucidate pathogenic pathways and screen for therapeutics capable of reversing pathological signatures.
We will generate region-specific brain organoids that model the neuronal activation deficits our lab has previously identified in in vivo studies to further understand the pathophysiology of cognitive impairment in MS.
By integrating transcriptomics data from these organoids with MS patient tissue, we will identify conserved transcriptional perturbations and define key pathological transcriptomes.
The validated 3D co-culture systems will then be used for the functional characterization of pathways driving glial dysregulation and neuronal dysfunction.
This project will establish a transformative human-specific model for studying MS. This platform will enable a deeper mechanistic dissection of MS and provide a direct pipeline for identifying and testing novel therapeutics.
Contact details
Dr Luca Peruzzotti Jametti (lp429@cam.ac.uk) – Neurology
Opportunities
This project is open to applicants who want to do a:
- PhD
- MPhil