Mesenchymal stem cells and hypoxia: Where are we?

Буравкова, Л. Б.; Andreeva, E. R.; Gogvadze, Vladimir; Zhivotovsky, Boris

doi:10.1016/j.mito.2014.07.005

Cited by 119 publications

(109 citation statements)

References 85 publications

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“…The microenvironment of MSCs in tissues is characterized by limited oxygen availability (hypoxia), which activates many stress and survival pathways in stem cells (Buravkova et al 2014). Indeed, O 2 levels in the bone marrow, from which MSCs were obtained in our study, remain as low as 1-6 % (Eliasson et al 2010;Chow et al 2001).…”

Section: Discussionmentioning

confidence: 74%

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells

Kim

Lee

et al. 2016

Cell Stress and Chaperones

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Culture of mesenchymal stem cells (MSCs) under ambient conditions does not replicate the low oxygen environment of normal physiological or pathological states and can result in cellular impairment during culture. To overcome these limitations, we explored the effect of hypoxia (1 % O 2 ) on the biological characteristics of MSCs over the course of different culture periods. The following biological characteristics were examined in human bone marrow-derived MSCs cultured under hypoxia for 8 weeks: proliferation rate, morphology, cell size, senescence, immunophenotypic characteristics, and the expression levels of stemness-associated factors and cytokine and chemokine genes. MSCs cultured under hypoxia for approximately 2 weeks showed increased proliferation and viability. During long-term culture, hypoxia delayed phenotypic changes in MSCs, such as increased cell volume, altered morphology, and the expression of senescence-associated-β-gal, without altering their characteristic immunophenotypic characteristics. Furthermore, hypoxia increased the expression of stemness and chemokine-related genes, including OCT4 and CXCR7, and did not decrease the expression of KLF4, C-MYC, CCL2, CXCL9, CXCL10, and CXCR4 compared with levels in cells cultured under normoxia. In conclusion, low oxygen tension improved the biological characteristics of MSCs during ex vivo expansion. These data suggest that hypoxic culture could be a useful method for increasing the efficacy of MSC cell therapies.

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Section: Discussionmentioning

confidence: 74%

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells

Kim

Lee

et al. 2016

Cell Stress and Chaperones

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“…Obviously, hypoxia can significantly modify MSC response to other microenvironmental signals. It has been clearly demonstrated that MSCs permanently expanded under tissue-related O 2 values (1-10%) display a significant alteration in their properties regardless of the tissue source [Buravkova et al, 2014;Madrigal et al, 2014]. Previously, we have demonstrated that stromal precursors from the stromal-vascular fraction of adipose tissue (adipose stromal cells, ASCs) under 5% O 2 displayed unchanged phenotype and viability, increased proliferative activity and attenuated osteogenic/adipogenic lineage commitment [Buravkova et al, 2009[Buravkova et al, , 2013.…”

Section: Introductionmentioning

confidence: 97%

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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“…However, there has been a great heterogeneity among experimental protocols differing in duration of exposure (0∼72h versus permanent) and severity of hypoxia (oxygen concentration varying from 0 to 5%) [7, 10, 13-18]. It’s even speculated that the hypoxic effects on BMSC behaviors are biphasic with acute short-term oxygen depletion provoking apoptosis while long-term hypoxic exposure being helpful for the maintenance of an undifferentiated state [19]. …”

Section: Introductionmentioning

confidence: 99%

“…Besides the well-documented beneficial effects of several growth factors such as vascular epithelial growth factor (VEGF), several cytokines expressed by BMSCs have been supposed to mediate the immunomodulation effect in cell-based therapy, including IFN-γ, TNF-α and IL-6 [21, 26]. It has been demonstrated that hypoxic culture enhances the secretion of paracrine factors and promotes therapeutic effects of BMSCs [19]. A microarray study revealed that hypoxic BMSCs increase the expression of several growth factors involved in cell proliferation, survival and angiogenesis, and the changes in cytokine expression profile are related to the improvement of therapeutic efficacy in the treatment of acute MI [14].…”

Section: Introductionmentioning

confidence: 99%

Permanently Hypoxic Cell Culture Yields Rat Bone Marrow Mesenchymal Cells with Higher Therapeutic Potential in the Treatment of Chronic Myocardial Infarction

Liu

Yang

Maureira

et al. 2017

Cell Physiol Biochem

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Background: The mismatch between traditional in vitro cell culture conditions and targeted chronic hypoxic myocardial tissue could potentially hamper the therapeutic effects of implanted bone marrow mesenchymal stem cells (BMSCs). This study sought to address (i) the extent of change to BMSC biological characteristics in different in vitro culture conditions and (ii) the effectiveness of permanent hypoxic culture for cell therapy in treating chronic myocardial infarction (MI) in rats. Methods: rat BMSCs were harvested and cultured in normoxic (21% O₂, n=27) or hypoxic conditions (5% O₂, n=27) until Passage 4 (P4). Cell growth tests, flow cytometry, and Bio-Plex assays were conducted to explore variations in the cell proliferation, phenotype, and cytokine expression, respectively. In the in vivo set-up, P3-BMSCs cultured in normoxia (n=6) or hypoxia (n=6) were intramyocardially injected into rat hearts that had previously experienced 1-month-old MI. The impact of cell therapy on cardiac segmental viability and hemodynamic performance was assessed 1 month later by 2-Deoxy-2[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) positron emission tomography (PET) imaging and pressure-volume catheter, respectively. Additional histomorphological examinations were conducted to evaluate inflammation, fibrosis, and neovascularization. Results: Hypoxic preconditioning significantly enhanced rat BMSC clonogenic potential and proliferation without altering the multipotency. Different profiles of inflammatory, fibrotic, and angiogenic cytokine secretion were also documented, with a marked correlation observed between in vitro and in vivo proangiogenic cytokine expression and tissue neovessels. Hypoxic-preconditioned cells presented a beneficial effect on the myocardial viability of infarct segments and intrinsic contractility. Conclusion: Hypoxic-preconditioned BMSCs were able to benefit myocardial perfusion and contractility, probably by modulating the inflammation and promoting angiogenesis.

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Mesenchymal stem cells and hypoxia: Where are we?

Cited by 119 publications

References 85 publications

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells

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

Permanently Hypoxic Cell Culture Yields Rat Bone Marrow Mesenchymal Cells with Higher Therapeutic Potential in the Treatment of Chronic Myocardial Infarction

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