Curcumin-Induced Heme Oxygenase-1 Expression Prevents H2O2-Induced Cell Death in Wild Type and Heme Oxygenase-2 Knockout Adipose-Derived Mesenchymal Stem Cells

International Journal of Molecular Sciences

Niels A. J. Cremers²  Ditte M. S. Lundvig²  Stephanie C. M. van Dalen¹  Rik F. Schelbergen¹  Peter L. E. M. van Lent¹  Walter A. Szarek³  Raymond F. Regan⁴  Carine E. Carels²  Frank A. D. T. G. Wagener² 

[1] Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands; E-Mails:;Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands; E-Mails:;Department of Chemistry, Queen’s University, Kingston, ON K7L 3N6, Canada; E-Mail:;Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; E-Mail:

关键词: adipose-derived mesenchymal stem cells;    oxidative stress;    apoptosis;    heme oxygenase;    carbon monoxide;   

DOI  :  10.3390/ijms151017974

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.