Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature lineages [bulkRNA-seq]

The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. First, we observed a notable mRNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs). Therefore, we employed tRNAsec gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis, revealing the insights into the protective roles of selenoproteins in preserving HSC stemness and facilitating B cell maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, reminiscent of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and Pre-B cells. While Trsp KO activated an antioxidant response transcription factor NRF2 across all hematopoietic cells, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in Pre-B cells of Trsp KO mice and the KO Pre-B/Pro-B cells displayed differentiation toward CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B to myeloid switch. Collectively, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and highlight the preventive potential of selenoproteins against aging-related hematopoietic alterations.