"The goal of my research is to characterise the heterogeneity of myeloid cells in the central nervous system and to model the dynamic changes of microglia using patient-derived pluripotent stem cells." Josef Priller
UK DRI Momentum Award
Prof Josef Priller is Chair of Brain Inflammation at the University of Edinburgh and Repair and Professor of Neuropsychiatry at Charité University Berlin. After studying medicine at the Max-Planck-Institute of Medicine and Psychiatry, he went on to specialise in neurology and psychiatry, with a particular interest in inflammation, bridging clinical work and basic research in the lab. He is a DRI Momentum Award holder, and will lead a novel research programme at the UK DRI at Edinburgh using stem cells to investigate microglia in neurodegenerative diseases.
1. At a glance
Using innovative new techniques to investigate microglia in neurodegenerative diseases
Prof Josef Priller is developing cutting-edge techniques to help advance research into the role of a type of brain cell called microglia in neurodegenerative diseases, including Alzheimer’s (AD) and Huntington’s disease (HD). Josef hopes to reveal key insights that will fuel the development of new treatments targeting these cells in disease.
Microglia are a specialised type of immune cell found within the brain. They act like sentry guards, exploring brain tissues for signs of damage or infections. When they spot a threat – foreign invaders, waste materials or dead cells, - they become active, ‘eating’ them up and alerting other immune cells for help. Activated microglia are a feature of many neurodegenerative diseases, but their exact role is currently not well-understood.
Microglia are also difficult to study and so researchers are developing innovative techniques, including one that will enable them to isolate a single microglial cell from human brain tissue and analyse its molecular profile in exquisite detail. Josef’s team will also generate microglia-like cells from human stem cells derived from skin or blood cells that they can grow in dishes for experiments. Using these new techniques, they will explore changes that happen to microglia in people with AD and HD.
2. Scientific goals
Microglia are the primary immune effector cells of the central nervous system (CNS). They originate from erythromyeloid progenitors in the yolk sac and are long-lived, highly specialized tissue macrophages. In contrast to most peripheral macrophage populations, microglia are not derived from hematopoietic stem cells in the bone marrow. Their development from immature KIT+ erythromyeloid progenitors in the yolk sac depends on the transcription factors PU.1, RUNX1, IRF8, as well as on the cytokines CSF-1 and IL-34.
Prof Josef Priller and his team have discovered that other myeloid populations in the CNS, such as perivascular and meningeal macrophages, also originate in the yolk sac and are long-lived tissue macrophages. The activation of CNS-resident myeloid cells is a cardinal feature of many neurodegenerative diseases, including Alzheimer’s disease (AD) and Huntington’s disease (HD). Notably, genes associated with increased risk for AD, such as TREM2 and CD33, are expressed by microglia and are implicated in phagocytosis and oxidative burst. In HD, microglial activation precedes the onset of clinical symptoms, and elevated levels of proinflammatory cytokines are found in the cerebrospinal fluid (CSF) and brain.
Recently, the mutant Huntingtin protein was found to promote pro-inflammatory transcriptional activation of microglia via myeloid lineage-determining factors PU.1 and C/EBPs. As human microglia are difficult to study, a number of groups have recently established protocols for the generation of microglia-like cells from human induced pluripotent stem cells (iPSCs). Microglia-like cells also develop within human cerebral organoids. However, these in vitro generated cells are still different from adult human microglia.
Main objectives and research goals:
The main objective of this programme, led by Prof Josef Priller, is to better characterize the role of microglia in neurodegenerative diseases, hopefully revealing novel therapeutic targets.
1. To establish a mass cytometry protocol to study human microglia from post-mortem brain tissue and fresh biopsies.
2. To establish a novel protocol to generate microglia-like cells from human iPSCs.
3. To explore the phenotypic changes of human microglia in AD and HD using post-mortem brain tissue and patient-derived iPSC lines.
3. Team members
Dr Amy Lloyd (Postdoctoral Researcher)
Dr David Munro (Postdoctoral Researcher)
Within UK DRI:
- Prof Siddharthan Chandran, UK DRI at Edinburgh
- Prof Giles Hardingham, UK DRI at Edinburgh
- Prof Barry McColl, UK DRI at Edinburgh
- Prof Tara Spires-Jones, UK DRI at Edinburgh
- Prof Sarah Tabrizi, UK DRI at UCL
Beyond UK DRI:
- Prof Anna Williams, University of Edinburgh
- Dr Veronique Miron, University of Edinburgh
- Dr Clare Pridans, University of Edinburgh
- Dr Dirk Sieger, University of Edinburgh
- Prof Neil Henderson, University of Edinburgh
- Prof Roger Barker, University of Cambridge
- Prof Marco Prinz, Institut für Neuropathologie, Freiburg
- Prof Alessandro Prigione, Max Delbrück Center for Molecular Medicine, Berlin
- Prof Erich Wanker, Max Delbrück Center for Molecular Medicine, Berlin
- Prof Ido Amit,The Weizmann Institute of Science, Rehovot, Israel
Neurodegeneration, neuroinflammation, microglia
Human iPSC-derived microglia, cell transplantation, mass cytometry, RNA-seq
7. Key publications
Priller J, Prinz M. Targeting microglia in brain disorders. Science. 2019 Jul 5;365(6448):32-33. doi: 10.1126/science.aau9100.
Böttcher, C., Schlickeiser, S., Sneeboer, M.A.M., Kunkel, D., Knop, A., Paza, E., Schulz, A., Mei, H.E., NBB-Psy, Hol, E.M., Siegmund, B., Glauben, R., Spruth, E.J., de Witte, L.D., and Priller J. Deep immune profiling of human brain microglia by multiplexed mass cytometry. Nat Neurosci. 2018; 13(2) DOI: 10.1038/nprot.2017.155
Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, Dillenburg A, Borger E, Soong D, Richardson JC, Kuhlmann T, Williams A, Pollard JW, des Rieux A, Priller J, Miron VE. Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat Neurosci. 2019 Jul;22(7):1046-1052. doi: 10.1038/s41593-019-0418-z.
Tabrizi, S.J., Leavitt, B.R., Landwehrmeyer, G.B., Wild, E.J., Saft, C., Barker, R.A., Blair, N.F., Craufurd, D., Priller, J., Rickards, H. and Rosser, A., 2019. Targeting Huntingtin expression in patients with Huntington’s Disease. New England Journal of Medicine. Jun 13;380(24):2307-2316. doi: 10.1056/NEJMoa1900907.
Masuda T, Sankowski R, Staszewski O, Böttcher C, Amann L, Sagar, Scheiwe C, Nessler S, Kunz P, van Loo G, Coenen VA, Reinacher PC, Michel A, Sure U, Gold R, Grün D, Priller J, Stadelmann C, Prinz M. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature. 2019 Feb;566(7744):388-392. doi: 10.1038/s41586-019-0924-x.