Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice
Year: 2026
Type: article
Abstract: Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (Grn)-deficient mice. We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.
Source: Molecular Neurodegeneration
Authors: Hayk Davtyan, Sarah Naguib, Yuliya Voskobiynyk, Jean Paul Chadarevian, Joia K. Capocchi, Jeannie L. Giacchino, Ghazaleh Eskandari-Sedighi, Vivianna DeNittis, Jeremy B. Ford, Ani Agababian, Jasmine Nguyen, Alina L. Chadarevian, Madison S. Sutherland, Sepideh Kiani Shabestari, Kayla Tran, Bret Holt, Alissa L. Nana, Jiasheng Zhang, Salvatore Spina, Man Ying Wong, Lea T. Grinberg, William W. Seeley, Eric Huang, Claire D. Clelland, Shiaoching Gong, Li Fan, Jeanne T. Paz, Mathew Blurton-Jones, Li Gan
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,090
Funders: California Institute for Regenerative Medicine, Larry L. Hillblom Foundation, BrightFocus Foundation, Cure Alzheimer's Fund, Gladstone Institutes, Rainwater Charitable Foundation, Alzheimer Society, NOMIS Stiftung, National Institutes of Health, University of California, San Francisco, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: The role of TREM2 in human microglial function and Alzheimer disease pathogenesis, G1464309150, Application of novel, stem-cell based approaches to study the mechanism of protective microglial response in Alzheimer’s Disease, G1835419597, G2979254290, G386819593, G3936990308, Examining the role of adaptive immunity in Alzheimer's Disease pathogenesis, G478057686, G5126935215, G5252881885, G6070640934, G6143810018, G6560329523, G7146800030, G7393974100, Using human iPSC derived microglia and chimeric models to examine the role of PLCG2 in Alzheimers disease, G7843301214, G9000044648, G9000105477, G9000111249, G9000115034, G9000260543, Role of Myeloid And CD4+ T Immune Cells in Post-Traumatic Plasticity, Manipulating DNA repair enzymes to examine the interactions between aging and Alzheimers disease with iPSC-derived microglia
OpenAlex ID: W7168787747