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

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.