Individuals with age-related clonal hematopoiesis (CH) are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive preclinical animal models to recapitulate the spectrum of human CH are lacking. Through error-corrected sequencing of 56 human CH/myeloid malignancy genes we identified natural CH driver mutations in aged rhesus macaques matching genes somatically mutated in human CH, with DNMT3A mutations being the most frequent. A CH model in young adult macaques was generated via autologous transplantation of CRISPR/Cas9-mediated gene-edited hematopoietic stem and progenitor cells (HSPCs), targeting the top human CH genes with loss-of-function (LOF) mutations. Long-term follow-up revealed reproducible and significant expansion of multiple HSPC clones with heterozygous TET2 LOF mutations, compared to minimal expansion of clones bearing other mutations. Although the blood counts of these CH macaques were normal, their bone marrows were hypercellular and myeloid-predominant. TET2-disrupted myeloid colony-forming units isolated from these animals showed a distinct hyperinflammatory gene expression profile compared to WT. In addition, mature macrophages purified from the CH macaques showed elevated NLRP3 inflammasome activity and increased interleukin (IL)-1b and IL-6 production. The model was used to test the impact of IL-6 blockage by tocilizumab, documenting a slowing of TET2 mutated expansion, suggesting that interruption of the IL-6 axis may remove the selective advantage of mutant HSPCs. These findings provide a model for examining the pathophysiology of CH and give insights into potential therapeutic interventions.
Host-associated microbiotas normally guide the trajectory of intrinsically encoded developmental programs, and dysbiosis is linked to neurodevelopmental disorders such as autism spectrum disorder.Recent work suggests that microbiotas modulate social phenotypes associated with these disorders, though developmental mechanisms linking microbiotas to social behavior are not well understood. We discovered that the zebrafish microbiota is required for normal social behavior. Using this model to examine neuronal features modulated by the microbiota during early development, we found that the microbiota restrains neurite complexity and targeting of specific forebrain neurons required for normal social behavior. The microbiota is also required for normal forebrain infiltration of microglia, the brain's resident phagocytes that remodel neuronal arbors, suggesting the microbiota modulates arborization via a neuro-immune route. Our work establishes a foundation for study of microbial and host mechanisms that link the microbiota and social behavior in an experimentally tractable model vertebrate.
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