Our research focusses on the function of innate immune cells, particularly macrophages and microglia. For this we exploit the ability of human induced Pluripotent Stem Cells (iPSC) to model innate immune cell function. We have pioneered methods for the differentiation of macrophages and microglia from iPSC, and their genetic manipulation. We use these models to better understand innate immune responses in disease, and especially the roles of Alzheimer’s and Parkinson’s-associated gene products in microglia function.
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PhosphoRab10 (yellow) coating a phagosome containing a yeast particle (zymosan, green) in a human iPSC-derived macrophage. Photo credit: Sally Cowley
Exosomes from human iPSC-derived microglia. Photo credit: Anne Hedegaard
We are the James & Lillian Martin Centre for Stem Cell Research.
Tissue-resident macrophages throughout the body have roles in immune surveillance and also in tissue homeostasis. Microglia, the brain resident cousins of macrophages, are a prime example of this, with roles including phagocytosis of dying neurons and trimming of incompetent synapses. Microglia are increasingly implicated in neurodegenerative disease – numerous Alzheimer’s, Parkinson’s and ALS-associated genes, identified from population and familial studies, have been shown to be expressed in microglia, and in several cases (eg TREM2) are not expressed in other brain cell types. Using the human iPSC models that we have developed, we have contributed to the understanding of the function of several of these gene products in macrophages/microglia, including alpha-synuclein, TREM2 and LRRK2 – disruption of these proteins induces cellular dysfunction converging around phago-lysosomal dynamics and vesicle trafficking. We are currently focussed on two main research themes: 1) to understand the subcellular pathways by which Alzheimer’s-associated aggregated tau protein is taken up, processed and released by microglia, and 2) to understand the role of the cGAS-STING pathway in double-stranded DNA detection by microglia, and its relevance to Parkinson’s.
The James and Lillian Martin Centre for Stem Cell Research also hosts a Stem Cell Facility, where we train researchers in the use of iPSC for modelling disease, particularly neurodegenerative disease and immunological disorders. We collaborate widely and share our expertise in iPSC derivation, iPSC genetic modification, and differentiation to myeloid, astrocyte, neuronal and lung lineages.
2023
C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.
Vahsen, B.F., Nalluru, S., Morgan, G.R., Farrimond, L., Carroll, E., Xu, Y., Cramb, K.M.L., Amein, B., Scaber, J., Katsikoudi, A., Candalija, A., Carcolé, M., Dafinca, R., Isaacs, A.M., Wade-Martins, R., Gray, E., Turner, M.R., Cowley, S.A., Talbot, K.
Nature Communications – 14(1):5898.
2022
Single-cell transcriptomics defines an improved, validated monoculture protocol for differentiation of human iPSC to microglia.
Washer, S.J., Perez-Alcantara, M., Chen, Y., Steer, J., James, W.S., Trynka, G., Bassett, A.R., Cowley, S.A.
Sci. Rep. – 12(1):19454.
2020
TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to knockout, yet only subtle functional phenotypes in human iPSC-derived macrophages.
Hall-Roberts, H., Agarwal, D., Obst, J., Smith, T.B., Monzón-Sandoval, J., Di Daniel, E., Webber, C., James, W.S., Mead, E., Davis, J.B., Cowley, S.A.
Alzheimers Res Ther. – 2(1):151.
2020
LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages.
Lee, H., Flynn, R., Sharma, I., Haberman, E., Carling, P.J., Nicholls, F.J., Stegmann, M., Vowles, J., Haenseler, W., Wade-Martins, R., James, W.S., Cowley, S.A.
Stem Cell Reports – 14(5):940-955.
2017
A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response.
Haenseler, W., Sansom, S.N., Buchrieser, J., Newey, S.E., Moore, C.S., Nicholls, F.J., Chintawar, S., Schnell, C., Antel, J.P., Allen, N.D., Cader, M.Z., Wade-Martins, R., James, W.S.* and Cowley, S.A.*
Stem Cell Reports – 8(6): 1727-1742.
2017
Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages.
Haenseler, W., Zambon, F., Lee, H., Vowles, J., Rinaldi, F., Duggal, G., Houlden, H., Gwinn, K., Wray, S., Luk, K.C., Wade-Martins, R., James, W.S. and Cowley, S.A.
Cell Reports – 7(1): 9003.