Gene Expression Linked to Reepithelialization of Human Skin Wounds

Abstract

Our understanding of the regulatory processes of reepithelialization during wound healing is incomplete. In an attempt to map the genes involved in epidermal regeneration and differentiation, we measured gene expression in formalin-fixed, paraffin-embedded standardized epidermal wounds induced by the suction-blister technique with associated nonwounded skin using NanoString technology. The transcripts of 139 selected genes involved in clotting, immune response to tissue injury, signaling pathways, cell adhesion and proliferation, extracellular matrix remodeling, zinc transport and keratinocyte differentiation were evaluated. We identified 22 upregulated differentially expressed genes (DEGs) in descending order of fold change (MMP1, MMP3, IL6, CXCL8, SERPINE1, IL1B, PTGS2, HBEGF, CXCL5, CXCL2, TIMP1, CYR61, CXCL1, MMP12, MMP9, HGF, CTGF, ITGB3, MT2A, FGF7, COL4A1 and PLAUR). The expression of the most upregulated gene, MMP1, correlated strongly with MMP3 followed by IL6 and IL1B. rhIL-1β, but not rhIL-6, exposure of cultured normal human epidermal keratinocytes and normal human dermal fibroblasts increased both MMP1 mRNA and MMP-1 protein levels, as well as TIMP1 mRNA levels. The increased TIMP1 in wounds was validated by immunohistochemistry. The six downregulated DEGs (COL7A1, MMP28, SLC39A2, FLG1, KRT10 and FLG2) were associated with epidermal maturation. KLK8 showed the strongest correlation with MKI67 mRNA levels and is a potential biomarker for keratinocyte proliferation. The observed gene expression changes correlate well with the current knowledge of physiological reepithelialization. Thus, the gene expression panel described in this paper could be used in patients with impaired healing to identify possible therapeutic targets.

Two-Dimensional Biodegradable Black Phosphorus Nanosheets Promote Large Full-Thickness Wound Healing through In Situ Regeneration Therapy

“…It was reported that MMP1 and MMP9 were related to ECs’ tubular morphogenesis . Also, MMP1 is unambiguously associated with re-epithelialization, playing a role in initiating the migration of keratinocytes in wound healing …”

RIG‐I contributes to keratinocyte proliferation and wound repair by inducing TIMP‐1 expression through NF‐κB signaling pathway

“…We then investigated the expression of Mmp9 in keratinocytes of WT and Ddx58 −/− mice and found no significant difference between these two groups. Further, we detected the expression of other Mmps such as Mmp3, Mmp8, and Mmp12 whose expression have been linked to re-epithelialization (Ågren et al, 2022;Chang & Nguyen, 2021) and found that there was no significant difference in the expression of these MMPs between WT and Ddx58 −/− mice suggesting that TIMP-1 induced by RIG-I exerts its proliferation function in an MMP-independent manner. Although the recognized TIMP-1 was always known as an inhibitor of MMPs, its role in cell proliferation appears to be more diverse and complex.…”

“…As mentioned above, TIMP-1 has a higher affinity for MMP9, and studies have demonstrated that an abnormally high MMP/TIMP ratio is often present in nonhealing wounds (Li et al, 2013;Muller et al, 2008). Therefore, to investigate whether the expression of Mmps such as Mmp9, Mmp3, Mmp8, and Mmp12 whose expression have been linked to re-epithelialization (Ågren et al, 2022;Chang & Nguyen, 2021) were dysregulated in skin injury of Ddx58 −/− mice, we performed qPCR and confirmed that there was no significant difference in these Mmps expression between WT mice and Ddx58 −/− mice (Supporting Information: Figure 3b). What's more, we detected the expression of Il-10, Il-1β, Il-6, and Tnf-α which could be regulated by RIG-I in the process of wound healing and found there was no significant difference in the expression of them between WT and Ddx58 −/− mice (Supporting Information: Figure 3c).…”

A multimodal, comprehensive characterization of a cutaneous wound model in healthy volunteers

“…Il‐6 is known to play a vital part in inflammation and activates both innate and the adaptive immune system 52 . In addition, it is known from literature that IL‐6 gene expression is elevated in reepithelization of human skin wounds 53 . Therefore, it was expected that IL‐6 would be elevated following the biopsy procedure.…”

“…52 In addition, it is known from literature that IL-6 gene expression is elevated in reepithelization of human skin wounds. 53 Therefore, it was expected that IL-6 would be elevated following the biopsy procedure.…”