Thesis Defense: Giang VU TO « The role of stress signals in hematopoietic aging »

Thesis Director: Dr Eirini TROMPOUKI

Abstract: Hematopoietic stem cells (HSCs) sustain lifelong blood and immune cell production by balancing self-renewal and differentiation. Aging of HSCs is characterized by an expansion of phenotypic HSCs in the bone marrow, activation of myeloid-biased transcriptional programs, accumulation of DNA damage and epigenetic alterations, and disruption of proteostasis, particularly pathways regulating cell-cycle control and lineage specification. HSC function is tightly regulated by the bone marrow niche, and exposure to inflammatory stimuli during early or midlife can induce long-lasting, aging-like hematopoietic changes, a phenomenon termed “inflammaging”. Aging is also associated with the derepression of transposable elements (TEs), or “jumping genes,” which can mobilize within the genome, perturb gene regulation, and generate cytosolic nucleic acid intermediates that trigger intrinsic antiviral responses. In this study, we investigated the role of MDA5, a cytosolic sensor of viral double-stranded RNA and endogenous RNAs, including those derived from TEs, in HSC aging. We hypothesized that loss of MDA5 would attenuate TE-driven inflammatory signaling, thereby preserving HSC function during aging. Consistent with this hypothesis, aged Mda5-deficient (Mda5^-/-) HSCs exhibited reduced accumulation of phenotypic HSCs, diminished transcriptional aging signatures, decreased myeloid bias, and enhanced regenerative capacity in both in vitro and in vivo assays. Mechanistically, these effects were associated with preserved activity of two key proteostasis pathways: PERK, which limits global protein synthesis under stress, and HSF1, which promotes protein quality control through chaperone induction and protein degradation. Maintenance of these pathways in Mda5^-/- HSCs likely contributes to improved proteostasis and functional integrity during aging. We further extended our analysis to assess the impact of infection and psychological stress on age-associated HSC phenotypes. Following stress exposure, wild-type mice displayed greater activation of both immune cells and HSCs compared to Mda5^-/- mice. These findings implicate MDA5 signaling as a critical regulator of HSC activation and differentiation in response to both physiological and psychological stress, with important implications for hematopoietic aging.