Comparing atmospheric and hypoxic cultured mesenchymal stem cell transcriptome: implication for stem cell therapies targeting intervertebral discs

Elabd, Christian; Ichim, Thomas E.; Miller, Kristina M.; Anneling, A.; Grinstein, V.; Vargas, V.; Silva, F. J.

doi:10.1186/s12967-018-1601-9

Cited by 47 publications

(42 citation statements)

References 72 publications

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“…Previous reports have shown that hypoxia altered the transcriptional profile of MSCs [32][33][34][35] . In particular, gene expression of Wharton's jelly-derived MSCs (WJ-MSCs) cultured in hypoxia and normoxia were compared and different profiles were observed.…”

Section: Discussionmentioning

confidence: 88%

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The Role of Hypoxia on the Neuronal Differentiation of Gingival Mesenchymal Stem Cells: A Transcriptional Study

et al. 2019

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Mesenchymal stem cells (MSCs) are widely used in stem cell therapy for regenerative purposes. Oral-derived MSCs, such as gingival MSCs (GMSCs), deriving from the neural crest seem more suitable to differentiate toward the neuronal lineage. In addition, the preconditioning of MSCs may improve their beneficial effects. Since it is known that hypoxia may influence stem cell properties, we were interested in evaluating the effects of hypoxia preconditioning on the neuronal differentiation of GMSCs. With this aim, we evaluated the transcriptional profile of GMSCs exposed to basal and neuroinductive medium both in normoxia and in cells preconditioned for 48 h in hypoxia. We compared their transcriptional profile using Next Generation Sequencing. At first we observed that hypoxia did not alter cell morphology compared with the GMSCs cultured in a normoxic condition. In order to understand hypoxia preconditioning effects on neuronal differentiation, we screened genes with Log2 fold change ≥2 using the database Cortecon, that collects gene expression data set of in vitro corticogenesis. We observed that hypoxia preconditioning induced the expression of more genes associated with different stages of cortical development. The common genes, expressed both in normoxia and hypoxia preconditioning, were involved in developmental and neuronal processes. Interestingly, a larger number of genes associated with development biology and neuronal process was expressed in GMSCs differentiated after hypoxia preconditioning compared with those in normoxia. In addition, hypoxic-preconditioned differentiated GMSCs showed a higher expression of nestin, PAX6, and GAP43. Our data demonstrated that hypoxia preconditioning enhanced the differentiation potential of GMSCs and induced the activation of a higher number of genes associated with neuronal development. In conclusion, hypoxia may be used to improve MSCs’ properties for stem cell therapy.

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Section: Discussionmentioning

confidence: 88%

“…Furthermore, in our study we only preconditioned GMSCs for 48 h in hypoxia before differentiation. Elabd et al showed that hypoxia preconditioning enhanced the MSCs' differentiation potential toward adipocyte and chondrocyte lineages 35 .…”

Section: Discussionmentioning

confidence: 99%

The Role of Hypoxia on the Neuronal Differentiation of Gingival Mesenchymal Stem Cells: A Transcriptional Study

et al. 2019

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“…The clonogenicity efficiency of MSCs grown at low [O 2 ] has been reported to be improved in comparison with 21% O 2 [42,43]. We developed an assay to determine whether improved clonogenicity was maintained when cells were switched from 3% to 21% O 2 .…”

Section: Clonogenicity Of Scaps In Vitromentioning

confidence: 99%

Isolation and Culture of Human Stem Cells from Apical Papilla under Low Oxygen Concentration Highlight Original Properties

Rémy

Ferraro

Salver

et al. 2019

Cells

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Stem cells isolated from the apical papilla of wisdom teeth (SCAPs) are an attractive model for tissue repair due to their availability, high proliferation rate and potential to differentiate in vitro towards mesodermal and neurogenic lineages. Adult stem cells, such as SCAPs, develop in stem cell niches in which the oxygen concentration [O 2 ] is low (3-8% compared with 21% of ambient air). In this work, we evaluate the impact of low [O 2 ] on the physiology of SCAPs isolated and processed in parallel at 21% or 3% O 2 without any hyperoxic shock in ambient air during the experiment performed at 3% O 2 . We demonstrate that SCAPs display a higher proliferation capacity at 3% O 2 than in ambient air with elevated expression levels of two cell surface antigens: the alpha-6 integrin subunit (CD49f) and the embryonic stem cell marker (SSEA4). We show that the mesodermal differentiation potential of SCAPs is conserved at early passage in both [O 2 ], but is partly lost at late passage and low [O 2 ], conditions in which SCAPs proliferate efficiently without any sign of apoptosis. Unexpectedly, we show that autophagic flux is active in SCAPs irrespective of [O 2 ] and that this process remains high in cells even after prolonged exposure to 3% O 2 .

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“…Using transcriptome analysis, Elabd et al. indicated that the following factors were significantly upregulated in hypoMSCs compared to norMSCs: 1) inflammation modulation, C-X-Cmotif chemokine ligand 5 (CXCL5), and strayfin (SFN); 2) cellular survival, migration, proliferation, glutathione peroxidase 3 (GPX3), LYL1 basic helix-loop-helix family member (LYL1), FES proto-oncogene, tyrosine kinase (FES), sperm-associated antigen 4 (SPAG4), transferrin receptor 2 (TR2), and thioredoxin interacting protein (TXNIP); 3) chondrolysis, cartilage metabolism; keratin 19 (KRT19), BARX homeobox1 (BARX1), MyoD family inhibitor (MDF1), dachsous cadherin-related 1 (DCHS1); and 4) vasculogenesis and angiogenesis, desmin, ras-interacting protein 1 (RASIP1), LYL1, thioredoxin-interacting protein (TXNIP), and FES [16]. In the present study, the levels of SPAG4, BARX1, CKCL5, KRT19, and TXNIP were >4 × , >4 × , >3.8 × , >3.6 × , and >2.5 × higher, respectively, in hypoMSCs than in norMSCs.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells cultured under hypoxic conditions had a greater therapeutic effect on mice with liver cirrhosis compared to those cultured under normal oxygen conditions

Kojima

Tsuchiya

Ogawa

et al. 2019

Regenerative Therapy

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BackgroundMesenchymal stem cells (MSCs) can be easily expanded. They can be acquired from medical waste such as adipose and umbilical cord tissues, are influenced by culturing conditions, and exert anti-inflammatory, antioxidant, anti-fibrotic, and angiogenic effects. We analyzed the multi-directional effects of MSCs cultured under hypoxic conditions and their underlying mechanisms in the treatment of liver cirrhosis in a mouse model.MethodsHuman bone marrow-derived MSCs cultured under hypoxic (5% O2; hypoMSCs) and normoxic (21% O2; norMSCs) conditions were compared by cap analysis of gene expression (CAGE) with or without serum from liver cirrhosis patients. The therapeutic effects of MSCs, including serum liver enzyme induction, fibrosis regression, and hepatic oxidative stress, were evaluated by injecting 1 × 106, 2 × 105, or 4 × 104 MSCs/mouse into the tail veins of mice with carbon tetrachloride (CCl4)-induced liver cirrhosis. Intravital imaging was performed with a two-photon excitation microscope to confirm the various MSC migration paths to the liver.ResultsCAGE analysis revealed that the RNA expression levels of prostaglandin E synthase (Ptges) and miR210 were significantly higher in hypoMSCs than in norMSCs. In vivo analysis revealed that both hypoMSCs and norMSCs reduced serum alanine aminotransferase, oxidative stress, and fibrosis compared to that in control mice in a dose-dependent manner. However, hypoMSCs had stronger therapeutic effects than norMSCs. We confirmed this observation by an in vitro study in which hypoMSCs changed macrophage polarity to an anti-inflammatory phenotype via prostaglandin E2 (PGE2) stimulation. In addition, miR210 reduced the rate of hepatocyte apoptosis. Intravital imaging after MSC administration showed that both cell types were primarily trapped in the lungs. Relatively a few hypoMSCs and norMSCs migrated to the liver. There were no significant differences in their distributions.ConclusionThe therapeutic effect of hypoMSCs was mediated by PGE2 and miR210 production and was greater than that of norMSCs. Therefore, MSCs can be manipulated to improve their therapeutic efficacy in the treatment of liver cirrhosis and could potentially serve in effective cell therapy. MSCs produce several factors with multidirectional effects and function as “conducting cells” in liver cirrhosis.

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Comparing atmospheric and hypoxic cultured mesenchymal stem cell transcriptome: implication for stem cell therapies targeting intervertebral discs

Cited by 47 publications

References 72 publications

The Role of Hypoxia on the Neuronal Differentiation of Gingival Mesenchymal Stem Cells: A Transcriptional Study

The Role of Hypoxia on the Neuronal Differentiation of Gingival Mesenchymal Stem Cells: A Transcriptional Study

Isolation and Culture of Human Stem Cells from Apical Papilla under Low Oxygen Concentration Highlight Original Properties

Mesenchymal stem cells cultured under hypoxic conditions had a greater therapeutic effect on mice with liver cirrhosis compared to those cultured under normal oxygen conditions

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