Capocchi, J. K. | Search bioRxiv

bioRxiv2026

Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice

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 microglia (iMG) into progranulin (Grn)-deficient mice. We find that wild-type, but not Grn-deficient, human iMG restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because 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. One Sentence SummaryOur study demonstrates that xenotransplantation of wild-type human iPSC-derived microglia into progranulin-deficient mice mitigates core neuropathological, network-level, and behavioral features of Frontotemporal Dementia.

neuroscience↗

bioRxiv2021

Prescribed versus wildfire impacts on exotic plants and soil microbes in California grasslands

O_LIPrescribed fire is often used as a management tool to decrease exotic plant cover and increase native plant cover in grasslands. These changes may also be mediated by fire impacts on soil microbial communities, which drive plant productivity and function. Yet, the ecological effects of prescribed burns compared to wildfires on either plant or soil microbial composition remain unclear. C_LIO_LIHere, we investigated the impacts of a spring prescribed fire versus a fall wildfire on plant cover and community composition and bacterial and fungal richness, abundance, and composition in a California grassland. We used qPCR of 16S and 18S to assess impacts on bacterial and fungal abundance and Illumina MiSeq of 16S and ITS2 to assess impacts on bacterial and fungal richness and composition. C_LIO_LIWildfire had stronger impacts than prescribed fire on microbial communities and both fires had similar impacts on plants with both prescribed and wildfire reducing exotic plant cover but neither reducing exotic plant richness. Fungal richness declined after the wildfire but not prescribed fire, but bacterial richness was unaffected by either. Yet increasing char levels in both fire types resulted in reduced bacterial and fungal biomass, and both fire types slightly altered bacterial and fungal composition. C_LIO_LIExotic and native plant diversity differentially affected soil microbial diversity, with native plant diversity leading to increased arbuscular mycorrhizal fungal richness while exotic plant diversity better predicted bacterial richness. However, the remainder of the soil microbial communities were more related to aspects of soil chemistry including cation exchange capacity, organic matter, pH and phosphorous. C_LIO_LISynthesis and applications. Understanding the different ecological effects of prescribed fires and wildfires on plant and soil communities are key to enhancing a prevalent management action and to guide potential management opportunities post wildfires. Our coupled plant and soil community sampling allowed us to capture the sensitivity of the fungal community to fire and highlights the importance of potentially incorporating management actions such as soil or fungal amendments to promote this critical community that mediates native plant performance. C_LI

ecology↗