Molecular neurodegenerationJul 17, 2026

Human stem cell–derived brain immune cells improve brain damage and circuit problems in mice lacking progranulin

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Updated Jul 18, 2026

Abstract

Engraftment of wild-type human microglia in progranulin-deficient mice restores brain-wide progranulin levels.

Progranulin haploinsufficiency is linked to disruptions in lysosomal function, lipid metabolism, and neuroimmune signaling.
Microglia show increased complement activation in response to progranulin loss, which may contribute to neuronal dysfunction.
Transplanting human microglial progenitors can normalize microglial gene expression in a progranulin-deficient environment.
Restoration of progranulin levels in microglia ameliorates pathological and behavioral issues associated with progranulin deficiency.
These findings suggest a crucial role for microglial progranulin in maintaining brain function in neurodegeneration.

Simplified

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.

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Competing interests

Declarations. Competing interests: M.B.J. is a co-founder and consultant for Savanna Biotherapeutics (formerly NovoGlia Inc.). L.G is founder and equity holder of Aeton Therapeutics, co-founder and equity holder of NeuroVanda Therapeutics; scientific advisor of Arvinas, NeuroLamda, and consultant for Retro Biosciences.

PubMed

Human stem cell–derived brain immune cells improve brain damage and circuit problems in mice lacking progranulin

Abstract

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Competing interests

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