title: Curcumin-induced heme oxygenase-1 expression prevents H2O2-induced cell death in wild type and heme oxygenase-2 knockout adipose-derived mesenchymal stem cells.
abstract: Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy.
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. niels.cremers@radboudumc.nl.
authors.forename: Niels A J
authors.initials: NA
authors.lastname: Cremers
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. ditte.lundvig@radboudumc.nl.
authors.forename: Ditte M S
authors.initials: DM
authors.lastname: Lundvig
authors.affiliation: Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. stephanie.vandalen@radboudumc.nl.
authors.forename: Stephanie C M
authors.initials: SC
authors.lastname: van Dalen
authors.affiliation: Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. rik.schelbergen@radboudumc.nl.
authors.forename: Rik F
authors.initials: RF
authors.lastname: Schelbergen
authors.affiliation: Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. peter.vanlent@radboudumc.nl.
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.affiliation: Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada. szarekw@chem.queensu.ca.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Szarek
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. Raymond.regan@jefferson.edu.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Regan
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. carine.carels@radboudumc.nl.
authors.forename: Carine E
authors.initials: CE
authors.lastname: Carels
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. frank.wagener@radboudumc.nl.
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001663:Bilirubin / Q000494:pharmacology; D001664:Biliverdine / Q000494:pharmacology; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D009942:Organometallic Compounds; D012333:RNA, Messenger; C447082:tricarbonyldichlororuthenium (II) dimer; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D003474:Curcumin; D001664:Biliverdine; D001663:Bilirubin; D000111:Acetylcysteine