Heterogeneity in Histiocytosis associated Neurodegeneration using iPSC models
Nicole Coufal, MD
University of California, San Diego
La Jolla, CA USA
Date of Award:
Amount of Award:
$51,000 (Founder’s Grant and Toughill Prize)
Neurodegeneration in patients with histiocytic disorders, especially Langerhans Cell Histiocytosis (LCH), is one of the most devastating, poorly understood, and treatment resistant long-term problems associated with LCH. LCH has been mostly modeled in mice, but there are substantial differences between the immune systems of mice and humans, especially in the resident immune cell of the brain, microglia. We have generated an induced pluripotent stem cell (iPSC) model of LCH, using blood samples from multi-system LCH patients that have been turned into stem cells in a dish that can differentiate into any of the cell type of the body. Using these iPSCs we have differentiated them to microglia and found that the BRAFV600E carrying microglia in LCH exhibit both early progenitor proliferation, and when they are more differentiated to microglia divide less, are hyperinflammatory and resistant to apoptosis (cell death). We also transplanted the LCH microglia into a humanized mouse model and found they cause profound neurodegeneration. How much these different differentiations states contribute to neurodegenerative LCH, how much patient genetic contribute to variability, and how the healthy immune cells react to the LCH cells is unknown. We will address these questions using our models by copying what happens in humans and introducing a mix of hematopoietic progenitors from the same person, mostly healthy with a small percentage of LCH cells and using a combination of stem cell biology, single cell sequencing, bioinformatics, and histology as a readout.
This project is relevant to histiocytic disorders because understanding how brain lesions develop and how diseased cells interact with healthy immune cells of the brain is key to identifying what LCH stage of cell differentiation to target, and how the healthy immune cells of the brain react and interact with LCH cells.
The overall goal of the proposal is to ultimately identify additional targets for LCH therapy and potential mechanisms for boosting the healthy microglial response with a goal of improving therapies for neurodegenerative LCH. The models generated through this proposal could potentially be utilized for generating preclinical data in vitro and in vivo to identify new therapies for neurodegenerative histiocytosis.