The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer

Hou, Chun‐Li; Shen, Lei; Huang, Qiang; Mi, Jianhong; Wu, Yangxiao; Yang, Mingcan; Zeng, Wen; Li, Li; Chen, Wen; Zhu, Chuhong

doi:10.1016/j.biomaterials.2012.09.022

Cited by 55 publications

(56 citation statements)

References 31 publications

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“…The clinical relevance of HO-1 induction in MSCs is further supported using in vivo models of tissue injury demonstrating improved MSC survival and tissue function [33,34,35,109,110,111,112]. …”

Section: Resultsmentioning

confidence: 99%

“…Induction of HO-1 has been demonstrated to improve MSC therapy in vivo by improving tissue functioning of the damaged organ, whereas inhibition of HO-activity worsened MSC therapy outcome in diverse pathologic conditions, such as ischemia reperfusion injury of the heart, pulmonary arterial hypertension, diabetes, and dermal wound healing [31,33,34,35,36,37,38,39,40]. It has been shown in vitro that HO-1 overexpression increases BM-derived MSC survival against oxidative stress, but the exact mechanism remains unknown [17,34].…”

Section: Introductionmentioning

confidence: 99%

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

Cremers

Lundvig

Dalen

et al. 2014

IJMS

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cremers

Lundvig

Dalen

et al. 2014

IJMS

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“…There may also be some enzymatically effected mechanisms in bilirubin-collagen in- -1 (HO-1) regulates collagen synthesis and might be affected from the imbalance in the oxidative-anti-oxidative status due to increased bilirubin levels. HO-1 plays a critical part in fibrogenic gene expression by antagonizing enhanced myocardial oxidative stress, angiogenesis, and wound healing (19,20).…”

Section: Discussionmentioning

confidence: 99%

Investigation of joint hypermobility in individuals with hyperbilirubinemia

et al. 2017

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Objective: Benign joint hypermobility syndrome refers to hypermobile individuals with musculoskeletal symptoms in the absence of any systemic rheumatic disease; its prevalence is approximately 0.5%. In animal studies, bilirubin has been shown to reduce fibrosis induced by bleomycin. It has been suggested that bilirubin leads to hypermobility that affects the structure or function of collagen. In addition, our observation is that hypermobility occurs more often in patients with indirect hyperbilirubinemia. In this study, we aimed to evaluate hypermobility in patients with indirect hyperbilirubinemia. Material and Methods:We recruited 120 consecutive patients with indirect hyperbilirubinemia from a tertiary gastroenterology outpatient clinic and examined them for hypermobility. Hypermobility was evaluated using the Beighton criteria, and other relevant clinical findings were recorded. In addition, a group of healthy individuals (n=107) without hyperbilirubinemia were included as controls.Results: The mean ages of the patients and controls were 33.4±12.9 and 36.2±11.2 years, respectively (p=0.09). In total, 100 (83%) patients and 78 (73%) controls were male (p=0.075). The mean indirect bilirubin levels were 1.44±0.66 mg/dL in the patient group and 0.37±0.18 mg/dL in the control group. Based on the Beighton score, 23 patients (19.2%) in the patient group and 3 (2.8%) individuals in the control group had joint hypermobility. The difference between the groups was statistically significant (p<0.001).Conclusion: According to the results of our study, findings of joint hypermobility are more frequent in patients with indirect hyperbilirubinemia than in controls.

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“…After 8 h of incubation at 37˚C in normoxic or hypoxic conditions, cells in the upper compartment were removed, while migrated cells in the lower compartment were washed three times with 0.01 mmol/l PBS, then fixed with 4% paraformaldehyde at room temperature for 4 h, stained with 0.5% crystal violet and imaged using the BX83 microscope. Image-Pro Plus 7.0 software (Media Cybernetics, Inc.) was used to calculate the number of cells and the cell migration rate, as described previously (20,21).…”

Section: Dna Fluorescence Proliferation Assay [5-ethynyl-2'-deoxyuridmentioning

confidence: 99%

“…Cells were cultured at 37˚C for 12 h under normoxic or hypoxic conditions and imaged using the BX83 microscope (Olympus Optical Co.) to observe cell morphology. Image-Pro Plus 7.0 software was used to count the number of endothelial cell tubes formed, as described previously (21).…”

Section: Dna Fluorescence Proliferation Assay [5-ethynyl-2'-deoxyuridmentioning

confidence: 99%

C-X-C motif chemokine ligand 8 promotes endothelial cell homing via the Akt-signal transducer and activator of transcription pathway to accelerate healing of ischemic and hypoxic skin ulcers

Shen

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. C-X-C motif chemokine ligand 8 (CXCL-8) promotes cell homing and angiogenesis. However, under hypoxic conditions, the role of CXCL-8 in the homing of human umbilical vein endothelial cells (HUVECs), and its effect on the healing of skin ulcers caused by ischemia and hypoxia remain unknown. In the current study, assays measuring cell proliferation, in vitro angiogenesis and cell migration were performed to evaluate alterations in the proliferation, angiogenic capacity and chemotaxis of HUVECs treated with CXCL-8 protein and/or an Akt inhibitor (AZD5363 group) under hypoxic conditions. Changes in the levels of Akt, signal transducer and activator of transcription 3 (STAT3), vascular endothelial growth factor (VEGF), malondialdehyde (MDA) and total-superoxide dismutase (total-SOD) were also detected by western blotting and ELISA. In addition, in vivo experiments were performed using a skin ulcer model in mice. Ischemic and hypoxic skin ulcers were created on the thighs of C57BL/6J mice, and the effects of CXCL-8 and HUVEC transplantation on the healing capacity of skin ulcers was determined by injecting mice with HUVECs and/or CXCL-8 recombinant protein (CXCL-8, HUVEC and HUVEC + CXCL-8 groups). Vascular endothelial cell homing, changes in vascular density and the expression of VEGF, SOD, EGF and MDA within the ulcer tissue were subsequently measured. In vitro experiments demonstrated that HUVEC proliferation, migration and tube forming capacity were significantly increased by CXCL-8 under hypoxic conditions. Additionally, levels of VEGF, MDA and SOD were significantly higher in the CXCL-8 group, though were significantly decreased by the Akt and STAT3 inhibitors. In vivo experiments demonstrated that the expression of VEGF, total-SOD and EGF proteins were higher in the skin ulcer tissue of mice treated with CXCL-8 + HUVEC, relative to mice treated with HUVECs alone. Furthermore, vascular endothelial cell homing and vascular density were significantly increased in the CXCL-8 + HUVEC group, indicating that combined use of HUVECs and CXCL-8 may promote the healing of ischemic skin ulcers. The present results demonstrate that CXCL-8 may stimulate vascular endothelial cells to secrete VEGF, SOD and other cytokines via the Akt-STAT3 pathway, which in turn serves a key regulatory role in the recruitment of vascular endothelial cells, reduction of hypoxia-related injury and promotion of tissue repair following hypoxic/ischemic injury.

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The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer

Cited by 55 publications

References 31 publications

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

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

Investigation of joint hypermobility in individuals with hyperbilirubinemia

C-X-C motif chemokine ligand 8 promotes endothelial cell homing via the Akt-signal transducer and activator of transcription pathway to accelerate healing of ischemic and hypoxic skin ulcers

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