To dissect the molecular pathways employed by tissue macrophages and their neighbouring cells in maintaining tissue integrity, and to understand the processes by which pathogens, inherited differences and environmental variables can disrupt them to cause disease, we employ human induced Pluripotent Stem Cell technology. We have developed cutting-edge methods for generating and genetically modifying iPSC and differentiating them to macrophages, microglia and neighbouring cell types. The following publications illustrate some of the results of this work:

C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9. Vahsen BF, Nalluru S, Morgan GR, Farrimond L, Carroll E, Xu Y, Cramb KML, Amein B, Scaber J, Katsikoudi A, Candalija A, Carcolé M, Dafinca R, Isaacs AM, Wade-Martins R, Gray E, Turner MR, Cowley SA, Talbot K. Nat Commun. 2023 Sep 22;14(1):5898.

Type I interferon receptor (IFNAR2) deficiency reveals Zika virus cytopathicity in human macrophages and microglia. Hanrath AT, Hatton CF, Gothe F, Browne C, Vowles J, Leary P, Cockell SJ, Cowley SA, James WS, Hambleton S, Duncan CJA. Front Immunol. 2022 Nov 11;13:1035532.

Single-cell transcriptomics defines an improved, validated monoculture protocol for differentiation of human iPSC to microglia. Washer SJ, Perez-Alcantara M, Chen Y, Steer J, James WS, Trynka G, Bassett AR, Cowley SA. Sci Rep. 2022 Nov 14;12(1):19454.

Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality. Sabate-Soler S, Nickels SL, Saraiva C, Berger E, Dubonyte U, Barmpa K, Lan YJ, Kouno T, Jarazo J, Robertson G, Sharif J, Koseki H, Thome C, Shin JW, Cowley SA, Schwamborn JC. Glia. 2022 Jul;70(7):1267-1288.

Human iPSC co-culture model to investigate the interaction between microglia and motor neurons. Vahsen BF, Gray E, Candalija A, Cramb KML, Scaber J, Dafinca R, Katsikoudi A, Xu Y, Farrimond L, Wade-Martins R, James WS, Turner MR, Cowley SA, Talbot K. Sci Rep. 2022 Jul 23;12(1):12606.

Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency. Gothe F, Stremenova Spegarova J, Hatton CF, Griffin H, Sargent T, Cowley SA, James W, Roppelt A, Shcherbina A, Hauck F, Reyburn HT, Duncan CJA, Hambleton S. J Allergy Clin Immunol. 2022 Feb 17:S0091-6749(22)00185-3

Differentiation of human induced pluripotent stem cells to authentic macrophages using a defined, serum-free, open-source medium. Vaughan-Jackson A, Stodolak S, Ebrahimi KH, Browne C, Reardon PK, Pires E, Gilbert-Jaramillo J, Cowley SA, James WS. Stem Cell Reports. 2021 Jul 13;16(7):1735-1748.

In vitro Quantitative Imaging Assay for Phagocytosis of Dead Neuroblastoma Cells by iPSC-Macrophages. Hall-Roberts H, Di Daniel E, James WS, Davis JB, Cowley SA. J Vis Exp. 2021 Feb 14;(168).

Genome-wide CRISPR/Cas9-knockout in human induced Pluripotent Stem Cell (iPSC)-derived macrophages. Navarro-Guerrero E, Tay C, Whalley JP, Cowley SA, Davies B, Knight JC, Ebner D. Sci Rep. 2021 Feb 19;11(1):4245.

Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart. Cahill TJ, Sun X, Ravaud C, Villa Del Campo C, Klaourakis K, Lupu IE, Lord AM, Browne C, Jacobsen SEW, Greaves DR, Jackson DG, Cowley SA, James W, Choudhury RP, Vieira JM, Riley PR. Development. 2021 Feb 3;148(3):dev194563.

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 TB, Monzón-Sandoval J, Di Daniel E, Webber C, James WS, Mead E, Davis JB, Cowley SA. Alzheimers Res Ther. 2020 Nov 16;12(1):151

Large-Scale Production of Human iPSC-Derived Macrophages for Drug Screening. Gutbier S, Wanke F, Dahm N, Rümmelin A, Zimmermann S, Christensen K, Köchl F, Rautanen A, Hatje K, Geering B, Zhang JD, Britschgi M, Cowley SA, Patsch C. Int J Mol Sci. 2020 Jul 7;21(13):4808.

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 PJ, Nicholls FJ, Stegmann M, Vowles J, Haenseler W, Wade-Martins R, James WS, Cowley SA. Stem Cell Reports. 2020 May 12;14(5):940-955.

RIPK1 is a critical modulator of both tonic and TLR-responsive inflammatory and cell death pathways in human macrophage differentiation. Buchrieser J, Oliva-Martin MJ, Moore MD, Long JCD, Cowley SA, Perez-Simón JA, James W, Venero JL. Cell Death Dis. 2018 Sep 24;9(10):973.

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. (2017). Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages. Scientific reports, 7(1).

Buchrieser J, James W, and Moore MD. Human Induced Pluripotent Stem Cell-Derived Macrophages Share Ontogeny with MYB-Independent Tissue-Resident Macrophages. Stem Cell Reports. 2017 Feb 14;8(2):334-345.

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. (2017). A highly efficient human pluripotent stem cell microglia model displays a Neuronal-Co-culture-Specific expression profile and inflammatory response. Stem cell reports, 8(6):1727-1742.

Kapellos, T. S., Taylor, L., Lee, H., Cowley, S. A., James, W. S., Iqbal, A. J., and Greaves, D. R. (2016). A novel real time imaging platform to quantify macrophage phagocytosis. Biochemical pharmacology. 116, 107-119.

Flynn, R., Grundmann, A., Renz, P., Hänseler, W., James, W. S., Cowley, S. A., and Moore, M. D. (2015). CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells. Experimental hematology, 43(10).

van Wilgenburg B, Moore MD, James WS and Cowley SA (2014) The productive entry pathway of HIV-1 in macrophages is dependent on endocytosis through lipid rafts containing CD4. PLoS ONE  DOI: 10.1371/journal.pone.0086071 

Wilgenburg Bv, Browne C, Vowles J, Cowley SA (2013) Efficient, Long Term Production of Monocyte-Derived Macrophages from Human Pluripotent Stem Cells under Partly-Defined and Fully-Defined Conditions. PLoS ONE 8(8): e71098. doi:10.1371/journal.pone.0071098

Jiang Y^*, Cowley SA^*, Siler U^* , Melguzo D, Tilgner K, Browne C, deWilton A, Pryzborski S, Saretzki G,James WS, Reichenbach J, Seger RA, Lako M and Armstrong L. ^*joint first authors. Derivation and functional analysis of patient specific induced pluripotent stem cells as an in vitro model of Chronic Granulomatous Disease. Stem Cells 2012 30(4):599-611.

Karlsson KR, Cowley S, Martinez FO, Shaw M, Minger SL, and James W. Homogeneous monocytes and macrophages from human embryonic stem cells following coculture-free differentiation in M-CSF and IL-3. Experimental Hematology 2008 36 1167–1175