Highlights
- •High-glucose environment altered the keratinocyte transcriptome responses to wounding.
- •In high-glucose cultivated keratinocytes, TNF, CYP24A1, NR4A3 and GGT1 were key overexpressed genes after wounding.
- •In high-glucose environment, wounding down-regulated keratinocyte differentiation and skin development, while up-regulated myeloid cell differentiation and myeloid leukocyte activation.
- •Keratinocyte samples from different individuals demonstrated diverse cellular responses to wounding in high-glucose environment.
- •The in-vitro model serves as a valuable tool to explore the heterogeneity in the pathomechanism of diabetic wounds among individuals and to facilitate the establishment of personalized therapies.
Abstract
Background
Impaired wound healing is a serious diabetes complication compromising patients’ quality
of life. However, the pathogenesis of diabetic wounds (DWs) remains incompletely understood.
Human epidermal keratinocyte (HEK) is the sentinel cell that initiates healing processes
after the epidermal integrity has been disrupted.
Objective
This study aimed to investigate the functional roles of HEKs in wound healing and
to identify candidate genes, signaling pathways and molecular signatures contributing
to the DWs.
Methods
HEKs were cultured in normal or high-glucose environment, followed by scratch, to
mimic the microenvironment of normal wounds and DWs. Subsequently, we performed RNA
sequencing and systematically analyzed the expression profiles by bioinformatics approaches.
Results
High-glucose environment altered the keratinocyte transcriptome responses to wounding.
In experimental model of DWs, we found that TNF, CYP24A1, NR4A3 and GGT1 were key overexpressed genes in keratinocytes and were implicated in multiple cellular
responses. Further analysis showed that wounding in high-glucose environment activated
G-protein-coupled receptor (GPCR) signaling, cAMP response element-binding protein
(CREB) signaling, and adrenomedullin signaling in keratinocytes, while dysregulated
skin development and immune responses as compared to their counterpart in normal glucose
settings.
Conclusion
This simplified in-vitro model serves as a valuable tool to gain insights into the
molecular basis of DWs and to facilitate establishment of personalized therapies in
clinical practice
Keywords
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Article info
Publication history
Accepted:
January 15,
2023
Received in revised form:
December 12,
2022
Received:
October 15,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
