Cited by 42Skin and Cellular Biology ResearchAdvancements in Transdermal Drug DeliveryDermatology and Skin Diseases

Human skin equivalents cultured under hypoxia display enhanced epidermal morphogenesis and lipid barrier formation

Open access
Mieremet, Arnout, Vázquez García, Adela, Boiten, Walter, van Dijk, Rianne, Gooris, Gert, Bouwstra, Joke A., El Ghalbzouri, Abdoelwaheb·2019·Scientific Reports

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-019-44204-4

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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)
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review