한빛사논문
Hyun-Jaung Sim1,2,4, Yong-Chan Kim1,3,4, Govinda Bhattarai1,2,4, Sae-Young Won1,3, Jeong-Chae Lee1,2, Byung-Hoon Jeong1,3 and Sung-Ho Kook1,2
1Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Republic of Korea.
2Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea.
3Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Republic of Korea.
4These authors contributed equally: Hyun-Jaung Sim, Yong-Chan Kim, Govinda Bhattarai.
Corresponding authors : Correspondence to Jeong-Chae Lee, Byung-Hoon Jeong or Sung-Ho Kook.
Abstract
Studies of PrPC-derived prion disease generally focus on neurodegeneration. However, little is known regarding the modulation of hematopoietic stem progenitor cells (HSPCs) that express PrPC in prion infection. Among bone marrow (BM) hematopoietic cells, hematopoietic stem cells (HSCs) strongly express PrPC. A bioassay revealed the presence of misfolded prion protein (PrPSc) 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 PrPC-positive but not PrPC-negative HSPC populations through a cell-autonomous mechanism. Notably, both PrPC-positive and PrPC-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.
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