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Lines of investigation
In the central nervous system, axons are ensheathed by myelin, a lipid-rich layer produced by oligodendrocytes that protects nerve fibres and accelerates action potential conduction. Myelin is not static; it is dynamic and adaptable, and its disruption is a common feature not only in demyelinating diseases such as multiple sclerosis (MS), but also with neurodevelopmental disorders (e.g., autism spectrum disorders), neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s), and ageing.
Oligodendroglial cells—oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes—are essential for myelin formation, maintenance, and regeneration. Unlike axons, lost myelin after demyelination can be restored through remyelination, a process driven by OPCs, adult stem cells of the CNS that, in response to damage, differentiate into new myelin-forming oligodendrocytes to regenerate myelin. However, this regenerative capacity declines in various diseases, mainly due to chronic exposure to inflammation and ageing.
Increasing evidence shows that both OPCs and mature oligodendrocytes respond to inflammation by adopting disease-associated phenotypes characterized by immune-related gene expression. However, the functional relevance of these genes in oligodendroglial cells and the molecular mechanisms governing oligodendroglial cell interaction with inflammation and the immune system remain poorly understood. Investigating these aspects is key to harnessing the potential of OPCs—the largest stem cell reservoir in the adult brain—and oligodendrocytes to modulate inflammation and enhance myelin regeneration.
Our group investigates the molecular, cellular, and systemic mechanisms that regulate myelin formation, maintenance, and regeneration in the central nervous system. Our goal is to understand why myelin regeneration fails in different pathologies, particularly in MS and ageing, to identify novel therapeutic targets that limit neuroinflammation and promote remyelination. To achieve this, we focus on studying how the interaction between inflammation, the immune system, and oligodendroglial cells modulates their regenerative and immunomodulatory capacity under physiological and pathological conditions. To this end, we use in vitro and in vivo models, including organotypic cultures, co-cultures of OPCs/oligodendrocytes with immune cells, and murine toxin-induced demyelination models (lysolecithin, cuprizone). By combining these models with molecular biology, histology, flow cytometry, and omics approaches (next-generation sequencing and epigenomics), we aim to identify factors and pathways that limit neuroinflammation and/or boost remyelination.
Representative Publications
- Ageing impairs the regenerative capacity of regulatory T cells in central nervous system remyelination. Guzmán de la Fuente A, Dittmer M, Heesbeen E, de la Vega Gallardo N, White J, Young A, McColgan T, Dashwood A, Mayne K, Cabeza-Fernández S, Falconer J, Rodriguez-Baena FJ, McMurran CE, Innayatullah M, Rawji KS, Franklin RJM, Dooley J, Liston A, Ingram R, Tiwari VK, Penalva R, Dombrowski Y and Fitzgerald DC. Nature Communications. 2024 15, Art. 1870 (2024) https://doi.org/10.1038/s41467-024-45742-w
- Glial cell alterations in diabetes-induced neurodegeneration. Llorián-Salvador, M., Cabeza-Fernández, S., Gomez-Sanchez, J.A, de la Fuente A. Cell. Mol. Life Sci. 2024 81: 47 https://doi.org/10.1007/s00018-023-05024-y
- Navigating the transition to Principal Investigator. Alerie G de la Fuente. Immunology and Cell Biology. 2024 102(9):Immunolgy and 766-774 https://doi.org/10.1111/imcb.12821
- Immune–stem cell crosstalk in the central nervous system: how oligodendrocyte progenitor cells interact with immune cells. Sonia Cabeza-Fernández, Jessica A White, Christopher E McMurran, José A Gómez-Sánchez, Alerie G de la Fuente. Immunology & Cell Biology. 2023 101 (1): 25-35 https://doi.org/10.1111/imcb.12610
- Ageing and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?. Katie Mayne, Jessica A. White, Christopher E. McMurran, Francisco J. Rivera & Alerie G. de la Fuente. Frontiers in Aging Neuroscience. 2020 https://doi.org/10.3389/fnagi.2020.572090
- Changes in the oligodendrocyte progenitor cell proteome with ageing. Alerie G. de la Fuente, Rayner M.L. Queiroz, Tanay Ghosh, Christopher E. McMurran, Juan F. Cubillos, Dwight E. Bergles, Denise C. Fitzgerald, Clare A. Jones, Kathryn S. Lilley, Colin P. Glover & Robin J.M. Franklin. Molecular & Cellular Proteomics. 2020 19(8): 1281-1302 https://doi.org/10.1074/mcp.RA120.002102
- The fatty acid binding protein FABP7 is required for optimal oligodendrocyte differentiation during myelination but not during remyelination. Sarah Foerster, Alerie Guzman de la Fuente, Yoshiteru Kagawa, Theresa Bartels, Yuji Owada & Robin J. M. Franklin. Glia. 2020 68(7):1410-1420 https://doi.org/10.1002/glia.23789
- Pericytes stimulate oligodendrocyte progenitor cell differentiation during CNS remyelination. Alerie Guzman De La Fuente, Simona Lange, Maria Elena Silva, Ginez A Gonzalez, Herbert Tempfer, Peter van Wijngaarden, Chao Zhao, Ludovica Di Canio, Andrea Trost, Lara Bieler, Pia Zaunmair, Peter Rotheneichner, Anna O'Sullivan, Sebastien Couillard-Despres, Oihana Errea, Maarja A Mäe, Johanna Andrae, Liqun He, Annika Keller, Luis F Bátiz, Christer Betsholtz, Ludwig Aigner, Robin J M Franklin & Francisco J Rivera. Cell Reports. 2017 20(8):1755-1764 https://doi.org/10.1016/j.celrep.2017.08.007
- Vitamin D receptor and retinoid X receptor heterodimer signalling regulates oligodendrocyte progenitor cell differentiation. Alerie Guzman de la Fuente, Oihana Errea, Peter van Wijngaarden, Ginez A Gonzalez, Christophe Kerninon, Andrew A Jarjour, Hilary J Lewis, Clare A Jones, Brahim Nait-Oumesmar, Chao Zhao, Jeffrey K Huang, Charles ffrench-Constant & Robin J M Franklin. Journal of Cell Biology. 2015 211(5):975-85 https://doi.org/10.1083/jcb.201505119
- Ageing impairs the regenerative capacity of regulatory T cells in central nervous system remyelination. Guzmán de la Fuente A, Dittmer M, Heesbeen E, de la Vega Gallardo N, White J, Young A, McColgan T, Dashwood A, Mayne K, Cabeza-Fernández S, Falconer J, Rodriguez-Baena FJ, McMurran CE, Innayatullah M, Rawji KS, Franklin RJM, Dooley J, Liston A, Ingram R, Tiwari VK, Penalva R, Dombrowski Y and Fitzgerald DC. Nature Communications. 2024 15, Art. 1870 (2024) https://doi.org/10.1038/s41467-024-45742-w
- Glial cell alterations in diabetes-induced neurodegeneration. Llorián-Salvador, M., Cabeza-Fernández, S., Gomez-Sanchez, J.A, de la Fuente A. Cell. Mol. Life Sci. 2024 81: 47 https://doi.org/10.1007/s00018-023-05024-y
- Navigating the transition to Principal Investigator. Alerie G de la Fuente. Immunology and Cell Biology. 2024 102(9):Immunolgy and 766-774 https://doi.org/10.1111/imcb.12821
- Regulatory T cells limit age-associated retinal inflammation and neurodegeneration. María Llorián-Salvador, Alerie G. de la Fuente, Christopher E. McMurran, Amy Dashwood, James Dooley, Adrian Liston, Rosana Penalva, Yvonne Dombrowski, Alan W. Stitt & Denise C. Fitzgerald. Molecular Neurodegeneration. 2024 19: 32 (2024) https://doi.org/10.1186/s13024-024-00724-w
- Regulatory T cell expansión prevents retinal degeneration in type 2 diabetes. María Llorián-Salvador, Daniel Pérez-Martínez, Miao Tang, Anna Duarri, Marta García-Ramirez, Anna Deàs-Just, Anna Álvarez-Guaita, Lorena Ramos-Pérez, Patricia Bogdanov, Jose A Gomez-Sanchez, Alan W Stitt, Cristina Hernández, Alerie G de la Fuente & Rafael Simó. Journal of Neuroinflammation. 2024 21(1):328 https://doi.org/10.1186/s12974-024-03323-0
- Novel therapeutic approaches to target neurodegeneration. Alerie G. de la Fuente, Silvia Pelucchi, Jerome Mertens, Monica Di Luca, Daniela Mauceri, Elena Marcello British Journal of Pharmacology. 2023 180 (13): 1651-1673 https://doi.org/10.1111/bph.16078
- Immune–stem cell crosstalk in the central nervous system: how oligodendrocyte progenitor cells interact with immune cells. Sonia Cabeza-Fernández, Jessica A White, Christopher E McMurran, José A Gómez-Sánchez, Alerie G de la Fuente. Immunology & Cell Biology. 2023 101 (1): 25-35 https://doi.org/10.1111/imcb.12610
- Brain-specific regulatory T cell expansion limits cognitive decline. Maria Llorián-Salvador, Alerie G. de la Fuente Trends in Molecular Medicine. 2023 29, Issue 7: 481-483 https://doi.org/10.1016/j.molmed.2023.05.001
- Autoantibodies and microglia: boon or bane? Michelle Naughton & Alerie G de la Fuente. Brain. 2021 4;144(8):2231-2233 https://doi.org/10.1093/brain/awab269
- Changes in the oligodendrocyte progenitor cell proteome with ageing. Alerie G. de la Fuente, Rayner M.L. Queiroz, Tanay Ghosh, Christopher E. McMurran, Juan F. Cubillos, Dwight E. Bergles, Denise C. Fitzgerald, Clare A. Jones, Kathryn S. Lilley, Colin P. Glover & Robin J.M. Franklin. Molecular & Cellular Proteomics. 2020 19(8): 1281-1302 https://doi.org/10.1074/mcp.RA120.002102
- Microglia require CD4 T cells to complete the fetal to adult transition. Emanuela Pasciuto, Oliver T Burton, Carlos P Roca, Vasiliki Lagou, Wenson D Rajan, Tom Theys, Renzo Mancuso, Raul Y Tito, Lubna Kouser, Zsuzsanna Callaerts-Vegh, Alerie G de la Fuente, Teresa Prezzemolo, Loriana G Mascali, Aleksandra Brajic, Carly E Whyte, Lidia Yshii, Anna Martinez-Muriana, Michelle Naughton, Andrew Young, Alena Moudra, Pierre Lemaitre, Suresh Poovathingal, Jeroen Raes, Bart De Strooper, Denise C Fitzgerald, James Dooley & Adrian Liston. Cell. 2020 182(3); 625-640e24 https://doi.org/10.1016/j.cell.2020.06.026
- The fatty acid binding protein FABP7 is required for optimal oligodendrocyte differentiation during myelination but not during remyelination. Sarah Foerster, Alerie Guzman de la Fuente, Yoshiteru Kagawa, Theresa Bartels, Yuji Owada & Robin J. M. Franklin. Glia. 2020 68(7):1410-1420 https://doi.org/10.1002/glia.23789
- Ageing and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?. Katie Mayne, Jessica A. White, Christopher E. McMurran, Francisco J. Rivera & Alerie G. de la Fuente. Frontiers in Aging Neuroscience. 2020 https://doi.org/10.3389/fnagi.2020.572090
- Aging restricts the ability of mesenchymal stem cells to promote the generation of remyelinating oligodendrocytes. Francisco J Rivera, Alerie G de la Fuente, Chao Zhao, Maria E Silva, Ginez A Gonzalez, Roman Wodnar, Martina Feichtner, Simona Lange, Oihana Errea, Eleni Priglinger, Anna O'Sullivan, Pasquale Romanelli, Janusz J Jadasz, Gabriele Brachtl, Richard Greil, Herbert Tempfer, Andreas Traweger, Luis F Bátiz, Patrick Küry, Sebastien Couillard-Despres, Robin J M Franklin & Ludwig Aigner. Glia. 2019 67(8): 1510-1525 https://doi.org/10.1002/glia.23624
- Pericytes stimulate oligodendrocyte progenitor cell differentiation during CNS remyelination. Alerie Guzman De La Fuente, Simona Lange, Maria Elena Silva, Ginez A Gonzalez, Herbert Tempfer, Peter van Wijngaarden, Chao Zhao, Ludovica Di Canio, Andrea Trost, Lara Bieler, Pia Zaunmair, Peter Rotheneichner, Anna O'Sullivan, Sebastien Couillard-Despres, Oihana Errea, Maarja A Mäe, Johanna Andrae, Liqun He, Annika Keller, Luis F Bátiz, Christer Betsholtz, Ludwig Aigner, Robin J M Franklin & Francisco J Rivera. Cell Reports. 2017 20(8):1755-1764 https://doi.org/10.1016/j.celrep.2017.08.007
- Vitamin D receptor and retinoid X receptor heterodimer signalling regulates oligodendrocyte progenitor cell differentiation. Alerie Guzman de la Fuente, Oihana Errea, Peter van Wijngaarden, Ginez A Gonzalez, Christophe Kerninon, Andrew A Jarjour, Hilary J Lewis, Clare A Jones, Brahim Nait-Oumesmar, Chao Zhao, Jeffrey K Huang, Charles ffrench-Constant & Robin J M Franklin. Journal of Cell Biology. 2015 211(5):975-85 https://doi.org/10.1083/jcb.201505119
- Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Muktha S Natrajan, Alerie G de la Fuente, Abbe H Crawford, Eimear Linehan, Vanessa Nuñez, Kory R Johnson, Tianxia Wu, Denise C Fitzgerald, Mercedes Ricote, Bibiana Bielekova & Robin J M Franklin. Brain. 2015 138(12): 3581-3597 https://doi.org/10.1093/brain/awv289
