Systems Biology of In Vitro Neuron and Microglia Formation

We do not understand how the adult brain works because of the lack of tools to study cellular interactions inside it. Organoids from stem cells are used but present two major drawbacks: 1-they do not allow to study the adult/aging brain, 2-the process of obtaining organoids containing glial cells takes several months. This project tackles these shortcomings by developing the generation of human microglial and neural cells through direct reprogramming of adult human fibroblasts. This way the cell product is obtained rapidly and maintains the aging signature of the starting cell. We put forward a shortcut to developing a 3D cell culture model encompassing both microglia and neurons from the same adult skin biopsy. This is the first-time neuron/microglia interactions will be studied in an aging human-based system. To achieve this, we will 1 screen for transcription factors to generate induced microglia and neurons from adult human dermal fibroblasts, 2 develop computational models of the gene regulatory network governing the direct conversion of skin fibroblasts to microglia and neurons 3 experimentally validate model predictions identifying the best reprogramming combinations. Develop a multi-scale model linked to the 3D cell culture. Importantly, the models and experiments will open up the possibility to study age-associated neuroinflammatory components of brain disorders, such as Parkinson’s and Alzheimer’s disease, on a patient-specific basis.