title: Hypoxia-induced expression of cellular prion protein improves the therapeutic potential of mesenchymal stem cells.
abstract: Mesenchymal stem cells (MSCs) are 'adult' multipotent cells that promote regeneration of injured tissues in vivo. However, differences in oxygenation levels between normoxic culture conditions (21% oxygen) and both the MSC niche (2-8% oxygen) and ischemic injury-induced oxidative stress conditions in vivo have resulted in low efficacy of MSC therapies in both pre-clinical and clinical studies. To address this issue, we examined the effectiveness of hypoxia preconditioning (2% oxygen) for enhancing the bioactivity and tissue-regenerative potential of adipose-derived MSCs. Hypoxia preconditioning enhanced the proliferative potential of MSCs by promoting the expression of normal cellular prion protein (PrPC). In particular, hypoxia preconditioning-mediated MSC proliferation was regulated by PrPC-dependent JAK2 and STAT3 activation. In addition, hypoxia preconditioning-induced PrPCregulated superoxide dismutase and catalase activity, and inhibited oxidative stress-induced apoptosis via inactivation of cleaved caspase-3. In a murine hindlimb ischemia model, hypoxia preconditioning enhanced the survival and proliferation of transplanted MSCs, ultimately resulting in improved functional recovery of the ischemic tissue, including the ratio of blood flow perfusion, limb salvage, and neovascularization. These results suggest that Hypo-MSC offer a therapeutic strategy for accelerated neovasculogenesis in ischemic diseases, and that PrPCcomprises a potential target for MSC-based therapies.
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Baltimore, AL 35294, USA.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
authors.forename: Yeo Min
authors.initials: YM
authors.lastname: Yoon
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Yun
authors.affiliation: Department of Internal Medicine, Soonchunhyang University, Seoul, Republic of Korea.|Hyonam Kidney Laboratory, Soonchunhyang University, Seoul, Republic of Korea.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Noh
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.|Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 330-930, Republic of Korea.
authors.forename: Sang Hun
authors.identifier: 0000-0002-6713-8229
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D053614:Janus Kinase 2; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D000072002:Prion Proteins / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D020127:Recovery of Function; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072002:Prion Proteins; D020011:Protective Agents; D050796:STAT3 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2