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Hematopoietic stem cell transplantation (HSCT) can replace endogenous microglia with circulation-derived macrophages but has high mortality. To mitigate the risks of HSCT and expand the potential for microglia replacement, we engineered an inhibitor-resistant CSF1R that enables robust microglia replacement. A glycine to alanine substitution at position 795 of human CSF1R (G795A) confers resistance to multiple CSF1R inhibitors, including PLX3397 and PLX5622. Biochemical and cell-based assays show no discernable gain or loss of function. G795A- but not wildtype-CSF1R expressing macrophages efficiently engraft the brain of PLX3397-treated mice and persist after cessation of inhibitor treatment. To gauge translational potential, we CRISPR engineered human-induced pluripotent stem cell–derived microglia (iMG) to express G795A. Xenotransplantation studies demonstrate that G795A-iMG exhibit nearly identical gene expression to wildtype iMG, respond to inflammatory stimuli, and progressively expand in the presence of PLX3397, replacing endogenous microglia to fully occupy the brain. In sum, we engineered a human CSF1R variant that enables nontoxic, cell type, and tissue-specific replacement of microglia.

 

Ookami [3] is a computer technology testbed supported by the United States National Science Foundation. It provides researchers with access to the A64FX processor developed by Fujitsu [17] in collaboration with RIKΞN [35, 37] for the Japanese path to exascale computing, as deployed in Fugaku [36], the fastest computer in the world [34]. By focusing on crucial architectural details, the ARM-based, multi-core, 512-bit SIMD-vector processor with ultrahigh-bandwidth memory promises to retain familiar and successful programming models while achieving very high performance for a wide range of applications. We review relevant technology and system details, and the main body of the paper focuses on initial experiences with the hardware and software ecosystem for micro-benchmarks, mini-apps, and full applications, and starts to answer questions about where such technologies fit into the NSF ecosystem.