Stem cell mobilization by hyperbaric oxygen

Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6068, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 05/2006; 290(4):H1378-86. DOI: 10.1152/ajpheart.00888.2005
Source: PubMed


We hypothesized that exposure to hyperbaric oxygen (HBO(2)) would mobilize stem/progenitor cells from the bone marrow by a nitric oxide (*NO) -dependent mechanism. The population of CD34(+) cells in the peripheral circulation of humans doubled in response to a single exposure to 2.0 atmospheres absolute (ATA) O(2) for 2 h. Over a course of 20 treatments, circulating CD34(+) cells increased eightfold, although the overall circulating white cell count was not significantly increased. The number of colony-forming cells (CFCs) increased from 16 +/- 2 to 26 +/- 3 CFCs/100,000 monocytes plated. Elevations in CFCs were entirely due to the CD34(+) subpopulation, but increased cell growth only occurred in samples obtained immediately posttreatment. A high proportion of progeny cells express receptors for vascular endothelial growth factor-2 and for stromal-derived growth factor. In mice, HBO(2) increased circulating stem cell factor by 50%, increased the number of circulating cells expressing stem cell antigen-1 and CD34 by 3.4-fold, and doubled the number of CFCs. Bone marrow *NO concentration increased by 1,008 +/- 255 nM in association with HBO(2). Stem cell mobilization did not occur in knockout mice lacking genes for endothelial *NO synthase. Moreover, pretreatment of wild-type mice with a *NO synthase inhibitor prevented the HBO(2)-induced elevation in stem cell factor and circulating stem cells. We conclude that HBO(2) mobilizes stem/progenitor cells by stimulating *NO synthesis.

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    • "Therefore, HBO can theoretically enhance the effect of chemo- and radiotherapy and reduce recurrence and metastasis by reducing the number of dormant cancer cells. In addition, HBO induces mobilization of stem/progenitor cells from the bone marrow into the peripheral circulation [7], [8], which improves patient recovery. Therefore, HBO not only enhances oxygen content in tissues but also promotes recovery with reduced side-effects and toxicity. "
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    ABSTRACT: Objectives Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO) therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC) but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. Methods Hepatoma cell lines (BEL-7402 and SK-Hep1) were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. Results Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation) in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. Conclusions We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression in hepatoma cells.
    PLoS ONE 06/2014; 9(6):e100814. DOI:10.1371/journal.pone.0100814 · 3.23 Impact Factor
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    • "These stem cells are believed to come from multiple sources including the bone marrow and periosteum (Colnot, 2009). HBO treatment increases the number of circulating hematopoietic stem cells (Thom et al., 2006) and endothelial precursor cells (Liu and Velazquez, 2008). However, there is no convincing evidence that BMSCs can be liberated from the bone marrow. "
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    ABSTRACT: We hypothesized that the effect of hyperbaric oxygen (HBO) on bone formation is increased via osteogenic differentiation of bone marrow stromal cells (BMSCs), which is regulated by Wnt3a/β-catenin signaling. Our in vitro data showed that HBO increased cell proliferation, Wnt3a production, LRP6 phosphorylation, and cyclin D1 expression in osteogenically differentiated BMSCs. The mRNA and protein levels of Wnt3a, β-catenin, and Runx2 were upregulated while those of GSK-3β were downregulated after HBO treatment. The relative density ratio (phospho-protein/protein) of Akt and GSK-3β was both up-regulated while that of β-catenin was down-regulated after HBO treatment. We next investigated whether HBO affects the accumulation of β-catenin. Our Western blot analysis showed increased levels of translocated β-catenin that stimulated the expression of target genes after HBO treatment. HBO increased TCF-dependent transcription, Runx2 promoter/Luc gene activity, and the expression of osteogenic markers of BMSCs, such as alkaline phosphatase activity, type I collagen, osteocalcin, calcium, and the intensity of Alizarin Red staining. HBO dose dependently increased the bone morphogenetic protein (BMP2) and osterix production. We further demonstrated that HBO increased the expression of vacuolar-ATPases, which stimulated Wnt3a secretion from BMSCs. Finally, we showed that the beneficial effects of HBO on bone formation were related to Wnt3a/β-catenin signaling in a rabbit model by histology, mechanical testing, and immunohistochemical assays. Accordingly, we concluded that HBO increased the osteogenic differentiation of BMSCs by regulating Wnt3a secretion and signaling.
    Stem Cell Research 11/2013; 12(1):260-274. DOI:10.1016/j.scr.2013.10.007 · 3.69 Impact Factor
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    • "Systemically, hyperbaric oxygen (HBO) increases bone marrow–derived endothelial progenitor cell mobilization. Although direct evidence of homing to the wound is lacking, there may be a correlation between increased circulating EPC and enhanced wound healing in diabetic patients (Goldstein et al., 2006; Thom et al., 2006; Gallagher et al., 2007, Milovanova et al., 2009). It is understood that ROS signaling is fundamental to HBOT (Thom, 2009) but the exact manner in which HBOT modulates ROS signaling pathways in the wound and protects ischemic tissue from oxidative stress remains unclear. "
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    ABSTRACT: Little is known about the impact of hyperbaric oxygen treatment (HBOT) on matrix metalloproteinase (MMP) production in pre-existing high-oxidant wounds. This study aimed to investigate whether HBOT modulates reactive oxygen species (ROS) and MMP regulation in ischemic wound tissue. Using a validated ischemic wound model, Sprague-Dawley rats were divided into four groups for daily treatment: HBOT, N-acetylcysteine (NAC), HBO and NAC, control (normoxia at sea level). High levels of iNOS, gp91-phox and 3-nitrotyrosine were detected in ischemic wounds, indicating high oxidant stress. HBOT not only increased antioxidant enzyme expression, such as Cu/Zn SOD, catalase, and glutathione peroxidase, but also significantly decreased pro-oxidant enzyme levels, such as iNOS and gp91-phox, thereby decreasing net oxygen radical production by means of negative feedback. This effect was blocked by NAC treatment in ischemic wounds. HBO-treated ischemic wounds also manifested reduced phosphorylation of ERK1/2, JNK, and c-Jun, indicating down-regulation of MAPKs. Furthermore, HBOT decreased the expression of several MMPs while simultaneously increasing tissue inhibitor of MMP (TIMP2). These results indicate that HBOT acts via the ROS/MAPK/MMP signaling axis to reduce tissue degeneration and improve ischemic wound healing.Journal of Investigative Dermatology accepted article preview online, 18 July 2013. doi:10.1038/jid.2013.301.
    Journal of Investigative Dermatology 07/2013; 134(1). DOI:10.1038/jid.2013.301 · 7.22 Impact Factor
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