William James

The resident macrophages of the brain – microglia – are critical in maintaining brain health, and when they are dysfunctional, diseases from dementias to neurocognitive disorders can result. For example, Alzheimer’s disease and Parkinson’s disease can in part be attributed to a failure of tissue homeostasis by microglia, in which they fail to clear misfolded proteins such as Abeta and Tau. In HIV-associated neurocognitive disorders  the sporadic reactivation of latent proviruses in microglia, seems to be the culprit. In both types of disease, repeated cycles of damage, inflammation and repair seem to underlie pathogenesis.

In respiratory infections, such as those by SARS-CoV-2, polarized epithelial cells of the upper and lower respiratory tract (ciliated cells and type 2 pneumocytes, respectively), which are the primary host of infection, can trigger local macrophages to limit viral spread, resolving infection, or induce the recruitment on infiltrating inflammatory macrophages, resulting in tissue damage and life-threatening disease.

In order to dissect the molecular pathways employed by tissue macrophages and their neighbouring cells to maintain tissue integrity and understand the processes by which pathogens, inherited differences and environmental variables can disrupt them to cause disease, we have developed cutting-edge methods for generating, genetically modifying, differentiating and studying human induced pluripotent stem cells. In addition to microglia and other tissue macrophages, we routinely generate hiPSC-derived cortical and dopaminergic neurons, astrocytes and respiratory epithelial cells. We are at the forefront of developing experimentally tractable yet physiologically authentic models of “tissue in a dish” to study these processes.