Hyperbaric oxygen promotes neural stem cell proliferation by activating vascular endothelial growth factor/extracellular signal-regulated kinase signaling after traumatic brain injury.
TL;DR: It is indicated that HBO may promote NSC proliferation by activating VEGF/ERK signaling and play a crucial role in neuroprotection after TBI.
Abstract: Hyperbaric oxygen (HBO) therapy and neural stem cell (NSC) transplantation can improve traumatic brain injury (TBI) clinically This study aimed to investigate the mechanism of HBO promoting NSC proliferation and neurological recovery after TBI Twenty-four Sprague-Dawley rats were divided randomly into three groups: a sham group, a TBI group (constructed using Feeney's free-fall method), and an HBO-treated TBI group Neurological function was evaluated by Neurological Severity Scores on days 1, 3, and 7, and we found that TBI-induced poor neurological function was improved by HBO On day 7 after TBI, we observed that TBI promoted NSC proliferation, migration to the lesion area, and the levels of vascular endothelial growth factor (VEGF), VEGFR2, Raf-1, MEK1/2, and phospho-extracellular signal-regulated kinase (ERK) 1/2 protein, which were further boosted by HBO, from immunohistochemistry, immunofluorescence, and Western blot experiments In vitro, cell injury was applied to NSCs isolated from neonatal Sprague-Dawley rats by the Cell Injury Controller II system Moreover, data from the BrdU Kit and Western blot showed that in-vitro HBO significantly accelerated NSC proliferation and the levels of proteins related to cell cycle and the VEGF/ERK pathway after cell injury, which was suppressed by the VEGFR2 inhibitor Taken together, this study indicated that HBO may promote NSC proliferation by activating VEGF/ERK signaling and play a crucial role in neuroprotection after TBI
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25 Jun 2020
TL;DR: Recurrent intermittent hyperoxia can induce many of the mediators and cellular mechanisms that are usually induced during hypoxia, called the hyperoxic-hypoxic paradox (HHP).
Abstract: Effective metabolism is highly dependent on a narrow therapeutic range of oxygen Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of gene expression, metabolic changes, and regenerative processes, including angiogenesis and stimulation of stem cell proliferation, migration, and differentiation The sensing of decreased oxygen levels (hypoxia) or increased oxygen levels (hyperoxia), occurs through specialized chemoreceptor cells and metabolic changes at the cellular level, which regulate the response Interestingly, fluctuations in the free oxygen concentration rather than the absolute level of oxygen can be interpreted at the cellular level as a lack of oxygen Thus, repeated intermittent hyperoxia can induce many of the mediators and cellular mechanisms that are usually induced during hypoxia This is called the hyperoxic-hypoxic paradox (HHP) This article reviews oxygen physiology, the main cellular processes triggered by hypoxia, and the cascade of events triggered by the HHP
72 citations
TL;DR: Exposure of osteogenic-differentiating MSCs to HBO under in vitro simulated inflammatory conditions enhances differentiation towards the osteogenic phenotype, providing evidence of the potential application of HBO in all those processes requiring bone regeneration.
Abstract: Hyperbaric oxygen (HBO) therapy has been reported to be beneficial for treating many conditions of inflammation-associated bone loss. The aim of this work was to in vitro investigate the effect of HBO in the course of osteogenesis of human Mesenchymal Stem Cells (MSCs) grown in a simulated pro-inflammatory environment. Cells were cultured with osteogenic differentiation factors in the presence or not of the pro-inflammatory cytokine Tumor Necrosis Factor-α (TNF-α), and simultaneously exposed daily for 60 min, and up to 21 days, at 2,4 atmosphere absolute (ATA) and 100% O2. To elucidate osteogenic differentiation-dependent effects, cells were additionally pre-committed prior to treatments. Cell metabolic activity was evaluated by means of the MTT assay and DNA content quantification, whereas osteogenic and vasculogenic differentiation was assessed by quantification of extracellular calcium deposition and gene expression analysis. Metabolic activity and osteogenic properties of cells did not differ between HBO, high pressure (HB) alone, or high oxygen (HO) alone and control if cells were pre-differentiated to the osteogenic lineage. In contrast, when treatments started contextually to the osteogenic differentiation of the cells, a significant reduction in cell metabolic activity first, and in mineral deposition at later time points, were observed in the HBO-treated group. Interestingly, TNF-α supplementation determined a significant improvement in the osteogenic capacity of cells subjected to HBO, which was not observed in TNF-α-treated cells exposed to HB or HO alone. This study suggests that exposure of osteogenic-differentiating MSCs to HBO under in vitro simulated inflammatory conditions enhances differentiation towards the osteogenic phenotype, providing evidence of the potential application of HBO in all those processes requiring bone regeneration.
34 citations
Cites background from "Hyperbaric oxygen promotes neural s..."
...The increase in VEGFA expression was accompanied by up-regulation of KDR, one of its two receptors [82,83]....
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01 Jun 2018
TL;DR: The innovative concept of stem cell preconditionsing, in tandem with brain preconditioning, is proposed as a promising regenerative pathway for maximizing the application of HBOT for ischemic stroke treatment.
Abstract: Stroke continues to be an extremely prevalent disease and poses a great challenge in developing safe and effective therapeutic options. Hyperbaric oxygen therapy (HBOT) has demonstrated significant pre-clinical effectiveness for the treatment of acute ischemic stroke, and limited potential in treating chronic neurological deficits. Reported benefits include reductions in oxidative stress, inflammation, neural apoptosis, and improved physiological metrics such as edema and oxygen perfusion, all of which contribute to improved functional recovery. This pre-clinical evidence has failed to translate into an effective evidence-based therapy, however, due in large part to significant inconsistencies in treatment protocols and design of clinical studies. While the medical community works to standardize clinical protocols in an effort to advance HBOT for acute stroke, pre-clinical investigations continue to probe novel applications of HBOT in an effort to optimize stroke neuroprotection. One such promising strategy is HBOT preconditioning. Based upon the premise of mild oxidative stress priming the brain for tolerating the full-blown oxidative stress inherent in stroke, HBOT preconditioning has displayed extensive efficacy. Here, we first review the pre-clinical and clinical evidence supporting HBOT delivery following ischemic stroke and then discuss the scientific basis for HBOT preconditioning as a neuroprotective strategy. Finally, we propose the innovative concept of stem cell preconditioning, in tandem with brain preconditioning, as a promising regenerative pathway for maximizing the application of HBOT for ischemic stroke treatment.
29 citations
Cites background from "Hyperbaric oxygen promotes neural s..."
...4.0 Implications of HBOT in Other Neurological and Non-neurological Conditions 4.1 HBOT in acute and chronic TBI A large number of studies have demonstrated the safety and effectiveness of HBOT in diverse models of traumatic brain injury (TBI), especially within the acute phase (Zhang et al., 2012; Lim et al., 2013; Wee et al., 2015; Lim et al., 2017)....
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...Clinical evaluations have revealed the potential of HBOT to confer neurorestorative effects in the chronic TBI brain as well; a recent study which initiated HBOT at 6 months to 27 years post-injury in human patients found upregulated angiogenesis and cerebral perfusion associated with improvement in memory, executive functions, information processing speed, and global cognitive scores as measured by an objective computerized exam (Tal et al., 2017)....
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...…upregulation of key regulatory molecules such as vascular endothelial growth factor (VEGF) (a downstream target of HIF-1α), its receptor (VEGFR2) (Yang et al., 2017), ERK (Jiang et al., 2015), and CREB (Zhu et al., 2004; Mendoza-Paredes et al., 2008) – all of which play roles in neurogenic…...
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...This combinatorial approach has been studied in a number of neurological and non-neurological contexts including TBI (Zhou et al., 2016), SCI (Geng et al., 2015) and diabetes mellitus (Estrada et al., 2008)....
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...HBOT may also promote neural stem cell proliferation via upregulation of key regulatory molecules such as vascular endothelial growth factor (VEGF) (a downstream target of HIF-1α), its receptor (VEGFR2) (Yang et al., 2017), ERK (Jiang et al., 2015), and CREB (Zhu et al., 2004; Mendoza-Paredes et al., 2008) – all of which play roles in neurogenic pathways (Lu et al., 2011)....
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18 Nov 2020
TL;DR: It is indicated that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.
Abstract: Introduction Aging is characterized by the progressive loss of physiological capacity. At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence. Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. The aim of the current study was to evaluate whether HBOT affects TL and senescent cell concentrations in a normal, non-pathological, aging adult population. Methods Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed. Results Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells which increased at the 30th session, 60th session and post HBOT by 25.68%±40.42 (p=0.007), 29.39%±23.39 (p=0.0001) and 37.63%±52.73 (p=0.007), respectively. There was a significant decrease in the number of senescent T helpers by -37.30%±33.04 post-HBOT (P
28 citations
TL;DR: Investigation of the influence of the hyperosmolarity of IVD on the proliferation and chondrogenic differentiation of NP-MSCs found that the relative hypo-osmotic condition prevailing in degenerative discs offers a more permissive microenvironment for NP- MSCs.
Abstract: Nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) are suitable cell candidates for intervertebral disc (IVD) regeneration. However, little work has been done to determine the proliferation and chondrogenic differentiation of NP-MSCs in the hyperosmotic microenvironment of IVD. This study aimed to investigate the influence of the hyperosmolarity of IVD on the proliferation and chondrogenic differ-entiation of NP-MSCs. NP-MSCs were cultured in media of 300, 400, 430, and 500 mOsm/L, mimicking the osmotic pressures of serious degenerative, moderately degenerative, and healthy IVD. Cell proliferation was measured by CCK-8 assay. The expression of aggrecan, collagen I, and collagen II were measured by gene and protein expression analysis. Alcian blue and dimethylmethylene blue assay were used to investigate the accumulation of sulfate glycosaminoglycan. The regulation role of extracellular signal-regulated kinase (ERK) pathway was also analyzed. The results showed that, compared to 300 mOsm/L, hyperosmolarity of healthy IVD (430 and 500 mOsm/L) inhibited the proliferation and chondrogenic differentiation of NP-MSCs. The relative hypoosmotic condition of moderately degenerative IVD (400 mOsm/L) led to great proliferation and chondrogenic differentiation capacity. The ERK pathway was activated by the hyperosmolarity; inhibition of the ERK pathway abolished the difference in cell proliferation between the 300 mOsm/L and the hyperosmotic conditions, and enhanced chondrogenic differentiation. In conclusion, hyperosmolarity of IVD had a significant impact on the proliferation and chondrogenic differentiation of NP-MSCs. The ERK pathway was involved in the inhibition of proliferation and chondrogenic differentiation of NP-MSCs by the hyperosmolarity of IVD. The relative hypo-osmotic condition prevailing in degenerative discs offers a more permissive microenvironment for NP-MSCs.
23 citations
Cites background from "Hyperbaric oxygen promotes neural s..."
..., 2018] and proliferation [Kim et al., 2015; Yang et al., 2017] of MSCs....
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..., 2018], and plays a vital role in the proliferation of MSCs [Kim et al., 2015; Yang et al., 2017]....
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...The extracellular signal-regulated kinase (ERK) pathway is a mitogen-activated protein kinase (MAPK) pathway, which is involved in the chondrogenic differentiation [Jiang et al., 2017; Wang et al., 2017a; Wu et al., 2018] and proliferation [Kim et al., 2015; Yang et al., 2017] of MSCs....
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...However, it has already been outlined from several stem cell systems that the ERK pathway is involved in chondrogenic differentiation [Jiang et al., 2017; Wang et al., 2017a; Wu et al., 2018], and plays a vital role in the proliferation of MSCs [Kim et al., 2015; Yang et al., 2017]....
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References
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TL;DR: Hyperbaric O2 has a more robust posttreatment effect than NBH on oxidative cerebral metabolism related to its ability to produce a brain tissue PO2 > or = 200 mm Hg, and it appears that O2 treatment for severe TBI is not an all or nothing phenomenon but represents a graduated effect.
Abstract: Object Oxygen delivered in supraphysiological amounts is currently under investigation as a therapy for severe traumatic brain injury (TBI). Hyperoxia can be delivered to the brain under normobaric as well as hyperbaric conditions. In this study the authors directly compare hyperbaric oxygen (HBO2) and normobaric hyperoxia (NBH) treatment effects. Methods Sixty-nine patients who had sustained severe TBIs (mean Glasgow Coma Scale Score 5.8) were prospectively randomized to 1 of 3 groups within 24 hours of injury: 1) HBO2, 60 minutes of HBO2 at 1.5 ATA; 2) NBH, 3 hours of 100% fraction of inspired oxygen at 1 ATA; and 3) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Brain tissue PO2, microdialysis, and intracranial pressure were continuously monitored. Cerebral blood flow (CBF), arteriovenous differences in oxygen, cerebral metabolic rate of oxygen (CMRO2), CSF lactate and F2-isoprostane concentrations, and bronchial alveolar lavage (BAL) fluid interleukin (IL)–8 an...
188 citations
TL;DR: Evidence is provided that VEGF increases SVZ neurogenesis and neuromigration, consistent with a possible role in repair, and suggests that in addition to its neuroprotective effects, V EGF enhances postischemic neuroGenesis, which could provide a therapeutic target for more chronic brain repair.
Abstract: New neurons are generated continuously in the subventricular zone and dentate gyrus of the adult brain Neuropathologic processes, including cerebral ischemia, can enhance neurogenesis, as can growth factors and other physiologic stimuli Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can promote neurogenesis, but it is unknown whether VEGF can enhance migration of newborn neurons toward sites of ischemic injury, where they might be able to replace neurons that undergo ischemic death In the present study we produced permanent focal cerebral ischemia in transgenic (Tg) mice that overexpress VEGF Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (Brdu) labeling and immunostaining for cell type-specific markers In VEGF-Tg mice, brains examined 7-28 days after cerebral ischemia showed markedly increased subventricular zone (SVZ) neurogenesis, chains of neuroblasts extending from the SVZ to the peri-infarct cortex, and an increase in the number of newly generated cortical neurons at 14-28 days after ischemia In concert with these effects, VEGF overexpression reduced infarct volume and improved postischemic motor function These findings provide evidence that VEGF increases SVZ neurogenesis and neuromigration, consistent with a possible role in repair Our data suggest that in addition to its neuroprotective effects, which are associated with improved outcome in the acute phase after cerebral ischemia, VEGF enhances postischemic neurogenesis, which could provide a therapeutic target for more chronic brain repair
184 citations
TL;DR: This study shows that expandable human neural stem/progenitor cells survive transplantation, and migrate, differentiate, and proliferate in the injured brain.
Abstract: Object. Cultures containing human neural stem and progenitor cells (neurospheres) have the capacity to proliferate and differentiate into the major phenotypes of the adult brain. These properties make them candidates for therapeutic transplantation in cases of neurological diseases that involve cell loss. In this study, long-term cultured and cryopreserved cells were transplanted into the traumatically injured rat brain to evaluate the potential for human neural stem/progenitor cells to survive and differentiate following traumatic injury. Methods. Neural stem/progenitor cell cultures were established from 10-week-old human forebrain. Immunosuppressed adult rats received a unilateral parietal cortical contusion injury, which was delivered using the weight-drop method. Immediately following the injury, these animals received transplants of neural stem/progenitor cells, which were placed close to the site of injury. Two or 6 weeks after the procedure, these animals were killed and their brains were examined...
133 citations
TL;DR: It is shown that adult hippocampal NSPCs secrete surprisingly large quantities of the essential growth factor VEGF in vitro and in vivo, which suggests that the function of adult neurogenesis may include the secretome of undifferentiated stem and progenitor cells.
Abstract: The adult hippocampus hosts a population of neural stem and progenitor cells (NSPCs) that proliferates throughout the mammalian life span. To date, the new neurons derived from NSPCs have been the primary measure of their functional relevance. However, recent studies show that undifferentiated cells may shape their environment through secreted growth factors. Whether endogenous adult NSPCs secrete functionally relevant growth factors remains unclear. We show that adult hippocampal NSPCs secrete surprisingly large quantities of the essential growth factor VEGF in vitro and in vivo. This self-derived VEGF is functionally relevant for maintaining the neurogenic niche as inducible, NSPC-specific loss of VEGF results in impaired stem cell maintenance despite the presence of VEGF produced from other niche cell types. These findings reveal adult hippocampal NSPCs as an unanticipated source of an essential growth factor and imply an exciting functional role for adult brain NSPCs as secretory cells.
124 citations
TL;DR: Hyperbaric oxygen therapy may serve as a promising neuroprotective strategy that when combined with other therapeutic targets for TBI patients which could improve long-term outcomes.
Abstract: Traumatic brain injury (TBI) is a major public health issue. The complexity of TBI has precluded the use of effective therapies. Hyperbaric oxygen therapy (HBOT) has been shown to be neuroprotective in multiple neurological disorders, but its efficacy in the management of TBI remains controversial. This review focuses on HBOT applications within the context of experimental and clinical TBI. We also discuss its potential neuroprotective mechanisms. Early or delayed multiple sessions of low atmospheric pressure HBOT can reduce intracranial pressure, improve mortality, as well as promote neurobehavioral recovery. The complimentary, synergistic actions of HBOT include improved tissue oxygenation and cellular metabolism, anti-apoptotic, and anti-inflammatory mechanisms. Thus HBOT may serve as a promising neuroprotective strategy that when combined with other therapeutic targets for TBI patients which could improve long-term outcomes.
72 citations