Human skin equivalents cultured under hypoxia display enhanced epidermal morphogenesis and lipid barrier formation
Open accessAbstract
Human skin equivalents (HSEs) are three-dimensional cell models mimicking characteristics of native human skin (NHS) in many aspects. However, a limitation of HSEs is the altered in vitro morphogenesis and barrier formation. Differences between in vitro and in vivo skin could have been induced by suboptimal cell culture conditions, of which the level of oxygen in vitro (20%) is much higher than in vivo (0.5–8%). Our aim is to study how external oxygen levels affect epidermal morphogenesis and barrier formation in HSEs. In the present study, fibroblast and keratinocyte monocultures, and HSEs were generated under 20% (normoxia) and 3% (hypoxia) oxygen level. In all cultures under hypoxia, expression of hypoxia-inducible factor target genes was increased. Characterization of HSEs generated under hypoxia using immunohistochemical analyses of morphogenesis biomarkers revealed a reduction in epidermal thickness, reduced proliferation, similar early differentiation, and an attenuated terminal differentiation program compared to normoxia, better mimicking NHS. The stratum corneum ceramide composition was studied with liquid chromatography coupled to mass spectrometry. Under hypoxia, HSEs exhibited a ceramide composition that more closely resembles that of NHS. Consequently, the lipid organization was improved. In conclusion, epidermal morphogenesis and barrier formation in HSEs reconstructed under hypoxia better mimics that of NHS.
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The 34 genes in the hypoxia gene module have been experimentally shown to be upregulated in response to hypoxia and/or possess a hypoxia response element in the promoter region.
“a manually curated list of 34 genes that have been experimentally shown to be upregulated in response to hypoxia and/or possess a hypoxia response element in the promoter region59–62”
From Single-cell transcriptomics of human-skin-equivalent organoids (2023) · cites this paper as [60]
The Results section ('Fibroblast and keratinocyte monocultures under hypoxia'; page unavailable) reports experimental upregulation of three pre-selected HIF target genes—GLUT1, PDK1 and VEGFA—under hypoxia. The Introduction says HIF complexes can bind hypoxia response elements, but the paper does not identify a curated set of 34 genes or establish that all 34 meet the stated criteria. (LLM, conf=0.88)
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Perticaroli, S., Meyers, J. L., Wireko, F. C., Akintelure, O., Webber, J. T., Cambron, R. T., Vierling, S., Sealschott, S. R., Wei, K., Smith, E., et al. (2020) · Journal of Raman Spectroscopy · doi:10.1002/jrs.5841 · Cited by 6 · see citing works
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Hausmann, C., Vogt, A., Kerscher, M. J., Ghoreschi, K., Schäfer‐Korting, M., & Zoschke, C. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.01.011 · Cited by 4 · see citing works
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ACE2 OVEREXPRESSION CHANGES THE SARS-COV-2 INFECTION PROFILE IN BEAS-2B CELLS
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ПОВСЕДНЕВНЫЙ КОСТЮМ РУБЕЖА XIX-XX ВВ. КАК ИСТОРИЧЕСКИЙ ИСТОЧНИК: ИСТОРИОГРАФИЧЕСКИЙ ОЧЕРК
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Advancing human skin models by integrating skin microbes for next-generation research
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Cryo-EM structure of human TMEM45A with a bound 2-Hydroxypalmitate
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- Authors
- Mieremet, A., Vázquez García, A., Boiten, W., van Dijk, R., Gooris, G., Bouwstra, J. A., & El Ghalbzouri, A.
- Affiliations
- Leiden University Medical Center (NL)
- Leiden University (NL)
- Corresponding author
- Mieremet, Arnout
- Venue
- Scientific Reports
- Published
- 2019-05-24
- Volume
- 9
- Issue
- 1
- Pages
- 7811-7811
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6534609
- OpenAlex
- W2946558878
- Cited by
- 42
- References
- 65
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 9 · 2023: 5 · 2022: 4 · 2021: 10 · 2020: 6 · 2019: 1 · 2014: 1
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Dutch Technology Foundation Applied and Engineering Sciences, grant number 13151.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Keywords
- human skin equivalents, hypoxia, epidermal morphogenesis, skin barrier formation, hypoxia-inducible factor, keratinocyte differentiation, terminal differentiation, stratum corneum, lipid organization, oxygen concentration, fibroblasts, keratinocytes, in vitro skin model
- MeSH terms
- Cells, Cultured, Epidermis, Fibroblasts, Humans, Skin, Keratinocytes, Cell Hypoxia, Tissue Engineering, Lipid Metabolism
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