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.

Gelatin positively regulates the immunosuppressive capabilitiesof adipose-derived mesenchymal stem cells

“…In vitro studies indicate that HO-1 expression was induced in MSCs by 4-methylcatecol (Lin et al, 2009), pitavastatin (Kawashiri et al, 2015), curcumin (Cremers et al, 2014), and cobalt protoporphyrin (Vanella et al, 2013). HO-1 overexpression enhances the resistance of MSCs to oxidative stress and serum deprivation (Kawashiri et al, 2015), as well as upregulating VEGF (Tsubokawa et al, 2010).…”

Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair

“…Thus, stem cell therapy is complicated by the limited number of cells surviving after administration at the wound site. This is due to the harsh conditions within the wound microenvironment characterized by a wealth of pro‐oxidative and pro‐inflammatory mediators, and only limited blood flow . Stem cells inducing anti‐apoptotic, anti‐inflammatory, and anti‐oxidative genes can better withstand these insults and have a better chance of surviving …”

“…Cytoprotective genes include enzyme systems such as HO‐1, glutathione S ‐transferase, dismutases, catalases, and peroxidases. HO‐1 induction improves stem cell survival and improves the outcome of stem cell therapy . In contrast, abrogation of HO‐activity decreases the efficacy of stem cell therapy .…”

“…This is due to the harsh conditions within the wound microenvironment characterized by a wealth of pro-oxidative and pro-inflammatory mediators, and only limited blood flow. [163][164][165] Stem cells inducing antiapoptotic, anti-inflammatory, and anti-oxidative genes can better withstand these insults and have a better chance of surviving. 163 Cytoprotective genes include enzyme systems such as HO-1, glutathione S-transferase, dismutases, catalases, and peroxidases.…”

“…[163][164][165] Stem cells inducing antiapoptotic, anti-inflammatory, and anti-oxidative genes can better withstand these insults and have a better chance of surviving. 163 Cytoprotective genes include enzyme systems such as HO-1, glutathione S-transferase, dismutases, catalases, and peroxidases. HO-1 induction improves stem cell survival and improves the outcome of stem cell therapy.…”