Immunity · 2025
Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Ошибки и ограничения
История · было → стало
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Aisenberg William H, O'Brien Carleigh A, Sangster Madison, Yaqoob Fazeela, Zhang Yuanchao, Temsamrit Brian, Thom Searlait, Gosse Luca, Chaluvadi Sai, Elfayomi Bilal, Lee Gavin, Polam Vidhur, Levitt Eli M, Liu Gary, Lombroso Sonia I, Nemec Kelsey M, Clowry Gavin, Nieves Cassaundra, Rawat Priyanka, Church Emily, Martinez Daniel, Shoffler Clarissa, Kancheva Daliya, Petucci Christopher, Taylor Deanne, Kofler Julia, Erskine Daniel, Movahedi Kiavash, Bennett Mariko L, Bennett F Chris
Аннотация
Krabbe disease, also named globoid cell (GC) leukodystrophy (GLD) for its distinct lipid-laden macrophages, is a severe leukodystrophy caused by galactosylceramidase (GALC) mutations. Hematopoietic stem cell transplant (HSCT) ameliorates disease and is associated with central nervous system (CNS) engraftment of GALC+ donor macrophages. Yet, the role of macrophages in GLD pathophysiology and HSCT remains unclear. Using single-cell sequencing, we revealed early interferon response signatures that preceded progressively severe macrophage dyshomeostasis and identified a molecular signature of GCs, which we validated in human brain specimens. Genetic depletion and direct microglia replacement by CNS monocyte injection rapidly replaced >80% of endogenous microglia with healthy macrophages in the twitcher (GalcW355∗) mouse model of GLD. Perinatal microglia replacement completely normalized transcriptional signatures, rescued histopathology, and doubled average survival. Overall, we uncovered distinct forms of microglial dysfunction and evidence that direct, CNS-limited microglia replacement improves a monogenic neurodegenerative disease, identifying a promising therapeutic target.