Hypoxia as a target for tissue specific gene therapy

Rhim, Taiyoun; Lee, Dong Yun; Lee, Minhyung

doi:10.1016/j.jconrel.2013.05.021

Cited by 61 publications

(41 citation statements)

References 135 publications

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“…The up-regulation of key 'stemness' genes (Oct3/4, Sox2 and Nanog) in ASCs under tissue-related O 2 was demonstrated [Fotia et al, 2014], indicating that in such conditions ASCs possess the phenotype of uncommitted progenitor cells, which is correlated with less pronounced osteo-and adipogenic induction under low O 2 , as mentioned above [Yamamoto et al, 2013;Fotia et al, 2014]. Thus, the functional activity of perivascular stromal cells in the 'natural habitat', in particular the response to acute hyp oxic stress after tissue damage [Hunt et al, 2000;Rhim et al, 2013], may differ significantly from that which can be expected based on our in vitro knowledge of MSC functions under ambient (20%) O 2 conditions. Though there are numerous papers which have demonstrated the benefits of short-term hypoxic preconditioning of 20% O 2 -expanded MSCs to improve their regenerative potential [Madrigal et al, 2014], there are no data on MSC/ASC on-site response on acute O 2 deprivation.…”

Section: Introductionmentioning

confidence: 87%

Response of Adipose Tissue-Derived Stromal Cells in Tissue-Related O<sub>2</sub> Microenvironment to Short-Term Hypoxic Stress

Andreeva

Lobanova

Udartseva

et al. 2014

Cells Tissues Organs

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A microenvironment low in O₂ (‘physiological' hypoxia) governs the functions of perivascular multipotent mesenchymal stromal cells, defining their involvement in tissue physiological homeostasis and regenerative remodelling. Acute hypoxic stress is considered as one of the important factors inducing tissue damage. Here, we evaluate the influence of short-term hypoxia (1% O₂ for 24 h) on perivascular adipose tissue-derived cells (ASCs) permanently expanded in tissue-related O₂ (5%) microenvironment. After hypoxic exposure, ASCs retained high viability, stromal cell morphology and mesenchymal phenotype (CD73+, CD90+, CD105+ and CD45-). Mild oxidative damage was unveiled as elevation of reactive oxygen species and thiobarbituric acid-active products, while no reduction in the activity of the antioxidant enzymes catalase and glutathione peroxidase and a 20% statistically significant increase in superoxide dismutase activity was detected. Expression of hypoxia-inducible factor (HIF)-1α and HIF-3α isoforms was differently regulated. HIF-1α displayed transient up-regulation, with maximum levels 30 min after acute hypoxic exposure, while HIF-3α was significantly up-regulated after 24 h. Up-regulation of ERK7, MEK1 and c-fos, and down-regulation of MKK6, p53, CCNA2, CCNB1 and CCNB2 were observed after 24 h of oxygen deprivation. Acute hypoxic exposure did not affect the gene expression of other mitogen-activated protein kinases (MAPKs) and MAPK kinases, MAPK/ERK kinase-interacting proteins, MAPK-activated transcription factors and scaffolding proteins. Significant stimulation of vascular endothelial growth factor α and interleukin-6 production was detected in ASC-conditioned medium. Thus, tissue O₂-adapted ASCs are resistant to hypoxic stress, which can ensure their effective involvement in the regeneration of tissue damage under significant oxygen deprivation.

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Section: Introductionmentioning

confidence: 87%

Response of Adipose Tissue-Derived Stromal Cells in Tissue-Related O<sub>2</sub> Microenvironment to Short-Term Hypoxic Stress

Andreeva

Lobanova

Udartseva

et al. 2014

Cells Tissues Organs

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“…Non-viral gene delivery systems overcome the safety issue but they miss out on the efficacy when evaluated for transfection. Moreover, as pointed out in another recent review (Rhim et al, 2013), hypoxia is not a suitable target for systemic gene delivery of hypoxia-inducible gene expression systems as it can easily be localized in organs with low physiological oxygen levels resulting in unwanted side effects. Therefore, dual specific expression systems should be considered for gene delivery approaches.…”

Section: Therapeutic Approaches To Exploit Hypoxic Tumor Microenvimentioning

confidence: 99%

Hypoxic tumor microenvironment: Opportunities to develop targeted therapies

Patel

Sant

2016

Biotechnology Advances

174

111

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Recent few years have seen great progress in understanding tumor biology and surrounding microenvironment. Solid tumors create regions with low oxygen levels, generally termed as hypoxic regions. These hypoxic areas offer a tremendous opportunity to develop targeted therapies. Hypoxia is not a random by-product of cellular milieu due to uncontrolled tumor growth; rather it is a constantly evolving participant in overall tumor growth and fate. This article reviews current trends and recent advances in drug therapies and delivery systems targeting hypoxia in the tumor microenvironment. In the first part, we give an account of important physicochemical changes and signaling pathways activated in the hypoxic microenvironment. This is then followed by various treatment strategies including hypoxia-sensitive signaling pathways and approaches to develop hypoxia-targeted drug delivery systems.

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“…Hypoxia is one of main pathologic characteristics of ischemic heart disease, MI [49]. In the consideration of hypoxia in the post-infarct I/R injury, we modified the human Relaxin 1 plasmid DNA ( R1 ) with 12 copies of hypoxia-responsive element (HRE), generating a HR1 (Suppl.…”

Section: Resultsmentioning

confidence: 99%

Human relaxin gene expression delivered by bioreducible dendrimer polymer for post-infarct cardiac remodeling in rats

Lee

Choi

et al. 2016

Biomaterials

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In consensus, myocardial infarction (MI) is defined as irreversible cell death secondary to prolonged ischemia in heart. The aim of our study was to evaluate the therapeutic potential of anti-fibrotic human Relaxin-expressing plasmid DNA with hypoxia response element (HRE) 12 copies (HR1) delivered by a dendrimer type PAM-ABP polymer G0 (HR1/G0) after MI on functional, hemodynamic, geometric, and cardiac extracellular matrix (ECM) remodeling in rats. HR1/G0 demonstrated significantly improved LV systolic function, hemodynamic parameters, and geometry on 1 wk and 4 wks after MI in rats, compared with I/R group. The resolution of regional wall motional abnormalities and the increased blood flow of infarct-related coronary artery supported functional improvements of HR1/G0. Furthermore, HR1/G0 polyplex showed favorable post-infarct cardiac ECM remodeling reflected on the favorable cardiac ECM compositions. Overall, this is the first study, which presented an advanced platform for the gene therapy that reverses adverse cardiac remodeling after MI with a HR1 gene delivered by a bioreducible dendrimer polymer in the cardiac ECM.

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Hypoxia as a target for tissue specific gene therapy

Cited by 61 publications

References 135 publications

Response of Adipose Tissue-Derived Stromal Cells in Tissue-Related O<sub>2</sub> Microenvironment to Short-Term Hypoxic Stress

Response of Adipose Tissue-Derived Stromal Cells in Tissue-Related O<sub>2</sub> Microenvironment to Short-Term Hypoxic Stress

Hypoxic tumor microenvironment: Opportunities to develop targeted therapies

Human relaxin gene expression delivered by bioreducible dendrimer polymer for post-infarct cardiac remodeling in rats

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