HSCs completely fail to regenerate following inflammatory challenge, leading to aged hematopoiesis

HSCs are thought to possess extensive self-renewal capacity, underlying their ability to sustain hematopoiesis throughout the lifetime of an organism. However, the functional HSC pool contracts in elderly humans, suggesting that the canonical concept of HSC self-renewal may be incorrect. Inflammatory stress results in depletion of functional HSCs in wild type(WT) mice, or exhaustion of the HSC pool and induction of aplastic anemia in a mouse model of Fanconi anemia (Walter et al, 2015, Nature). To assess regenerative self-renewal of HSCs in the native setting, WT mice were subject to polyinosinic:polycytidylic acid(pI:C) dose escalation, to mimic chronic viral infection and inflammation. 1-3 rounds of pI:C had no effect on peripheral blood(PB) parameters, but the frequency of functional HSC progressively decreased approximately 2-fold per round of pI:C, as assessed by competitive repopulation. The in-vitro clonal proliferative capacity of HSCs also decreased and was skewed towards depletion of multi-potent clones. To directly assess the regenerative capacity of HSCs in vivo, mice were treated with 3 rounds of pI:C followed by 5-20 weeks of recovery. Competitive repopulation and limiting dilution assays indicated absolutely no evidence for HSC recovery with increasing time post-treatment. Likewise, pI:C mediated depletion of endogenous HSCs facilitated transplantation into these mice up to 20 weeks post-treatment, in the absence of any irradiation conditioning. Taken together, inflammatory stress led to a progressive and irreversible depletion of functional HSCs, suggesting that cumulative exposure to environmental agonists might be a mediator of age-associated pathologies. Indeed, aged WT mice treated with pI:C in early to mid-life displayed PB cytopenias, BM hypoplasia and increased adipogenesis, that are clinical features of aged human hematopoiesis which never spontaneously develop in laboratory mice. We propose that environmental agonists are a missing ingredient in the study of aged hematopoiesis in experimental mice, and hypothesize that HSCs are not preserved during ageing by engaging in serial self-renewal divisions, but rather by extended quiescence.