Chronic Inflammation Induces a Molecular and Functional State Divergent from Physiological Aging in Hematopoietic Stem Cells 2328049

Abstract Introduction Chronic inflammation is postulated to drive hematopoietic stem cell (HSC) aging, largely based on functional decline observed in transplantation assays. However, transplantation imposes severe regenerative stress that may mask native HSC behaviors. It remains unclear whether chronic inflammatory stress truly recapitulates the physiological aging program in situ. We revisited this paradigm using lineage tracing model to distinguish inflammatory adaptation from genuine senescence. Methods We utilized the DARLIN mouse model for high-resolution in situ lineage tracing. Mice received multiple doses of LPS or Poly(I:C) over 2 months to mimic the chronic inflammation and followed by another 2-month break. We integrated clonal tracking with bulk RNA-seq, ATAC-seq, and scRNA-seq to profile the functional and epigenetic landscapes of inflammation-exposed HSCs compared to naturally aged HSCs. Aged mice were also treated to assess if chronic inflammation exacerbates HSC aging signatures. Results While inflammation-treated HSCs showed reduced self-renewal in transplantation, in situ barcoding revealed sustained multilineage output without the myeloid skewing characteristic of aging. Multi-omics demonstrated that chronic inflammation induces an activated state–marked by increased chromatin accessibility at lymphocyte loci and expansion of primed HSC subpopulations–diametrically opposing the repressive program of physiological aging. Furthermore, chronic inflammatory challenge in aged mice re-activated quiescent HSCs to enter the cell cycle rather than exacerbating the aging signature. Conclusion These findings uncouple chronic inflammation from physiological aging in HSC, identifying it as a distinct, active host defense response that preserves differentiation flux despite compromising regenerative potential under transplantation stress. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)