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

Authors

Niels A J Cremers, Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life SciencesFollow
Ditte M S Lundvig, Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences
Stephanie C M van Dalen, Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences
Rik F Schelbergen, Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences
Peter L E M van Lent, Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences
Walter A Szarek, Department of Chemistry, Queen’s University
Raymond F. Regan, Department of Emergency Medicine, Thomas Jefferson UniversityFollow
Carine E Carels, Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences
Frank A D T G Wagener, Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Radboud Institute for Molecular Life SciencesFollow

Document Type

Article

Publication Date

10-8-2014

Comments

This article has been peer reviewed. It was published in: International Journal of Molecular Sciences.

Volume 15, Issue 10, 8 October 2014, Pages 17974-17999.

The published version is available at DOI: 10.3390/ijms151017974

Copyright © 2014 MDPI

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.

Recommended Citation

Cremers, Niels A J; Lundvig, Ditte M S; van Dalen, Stephanie C M; Schelbergen, Rik F; van Lent, Peter L E M; Szarek, Walter A; Regan, Raymond F.; Carels, Carine E; and Wagener, Frank A D T G, "Curcumin-Induced Heme Oxygenase-1 Expression Prevents H2O2-Induced Cell Death in Wild Type and Heme Oxygenase-2 Knockout Adipose-Derived Mesenchymal Stem Cells." (2014). Department of Emergency Medicine Faculty Papers. Paper 35.
https://jdc.jefferson.edu/emfp/35

PubMed ID

25299695