Prion infection modulates hematopoietic stem/progenitor cell fate through cell-autonomous and non-autonomous mechanisms

Studies of PrP(C)-derived prion disease generally focus on neurodegeneration. However, little is known regarding the modulation of hematopoietic stem progenitor cells (HSPCs) that express PrP(C) in prion infection. Among bone marrow (BM) hematopoietic cells, hematopoietic stem cells (HSCs) strongly express PrP(C). A bioassay revealed the presence of misfolded prion protein (PrP(Sc)) in BM cells derived from prion-infected mice; these BM cells demonstrated reproducible prion infectivity. At 5 months after infection with ME7, mice exhibited a significant decrease in the number of HSPCs. This decrease was mainly driven by increased apoptotic cell death, rather than cell cycle progression and senescence, in PrP(C)-positive but not PrP(C)-negative HSPC populations through a cell-autonomous mechanism. Notably, both PrP(C)-positive and PrP(C)-negative HSCs underwent cellular senescence, as indicated by high levels of senescence-associated factors and deficits in repopulation and self-renewal capacities at 7 months after infection. Senescence of HSCs occurred in the ME7-impaired BM microenvironment with aging phenotypes through non-cell autonomous mechanisms. These data provide novel evidence that prion infection differentially modulates HSC fate through both cell-autonomous and non-autonomous mechanisms.