MicroRNA-200b/c-3p regulate epithelial plasticity and inhibit cutaneous wound healing by modulating TGF-β-mediated RAC1 signaling

Abstract

Cutaneous wound healing is pivotal for human skin to regain barrier function against pathogens. MicroRNAs (miRNAs) have been found to play regulatory roles in wound healing. However, the mechanism of miRNA regulation remains largely unknown. In this study, we focused on microRNA-200b/c-3p (miR-200b/c-3p) whose expression was abundant in intact epidermis, but dramatically decreased in skin wounds. In silico prediction identified RAC1 as a potential miR-200b/c-3p target. Luciferase reporter assay confirmed that miR-200b/c-p repressed RAC1 by direct targeting to its mRNA 3′UTR. Consistently, miR-200b/c-3p expression was discordantly related to RAC1 protein level during wound healing. Forced miR-200b/c-3p expression repressed RAC1 and inhibited keratinocyte migration as well as re-epithelialization in a mouse back skin full-thickness wound healing model. Mechanistically, miR-200b/c-3p modulated RAC1 to inhibit cell migration by repressing lamellipodia formation and intercellular adhesion dissolution in keratinocytes. Furthermore, we found that TGF-β1, which was highly expressed in skin wounds, contributed to the downregulation of miR-200b/c-3p in wound edge keratinocytes. Taken together, miR-200b/c-3p-mediated RAC1 repression inhibited keratinocyte migration to delay re-epithelialization. TGF-β1 induction attenuated miR-200b/c-3p regulation of RAC1 signaling in cutaneous wounds and the repression of miR-200b/c-3p accelerated keratinocyte migration to promote wound healing. Our data provide new insight into how miR-200b/c-3p affects keratinocyte migration and highlight the potential of miR-200b/c-3p targeting for accelerating wound healing.

Unilateral zebrafish corneal injury induces bilateral cell plasticity supporting wound closure

“…These observations can be viewed within the larger perspective of cell plasticity in organ regeneration. By attaining a higher degree of plasticity, terminally differentiated cells appear to develop the capacities to heal a tissue or an organ, as it has been observed in relation to skin 55 , the intestine 56 , and the vascular system 57 , among others. It is notable, however, that Pax6 modulation has not been studied in the early stages of wound closure in mouse models, although an increase of Pax6 expression later on in the healing process was reported 58 .…”

Unilateral corneal insult in Zebrafish results in a bilateral cell shape and identity modification, supporting wound closure

“…These observations can be viewed in the larger perspective of cell plasticity in organ regeneration. By reaching a higher degree of plasticity, terminally differentiated cells seem to develop the abilities to heal a tissue or an organ, as seen in skin (Tang H et al, 2020), intestine (Kurokawa et al, 2020), and vascular system (Tombor et al, 2021), among others. Further investigations could shed new light on the molecular modulations of cell identity and phenotype required during wound healing and tissue regeneration, not only in cornea, but in most organs.…”

Nanotechnology‐Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID‐19 Vaccines

“…The microRNA‐200b/c‐3p expression is abundant in the intact epidermis; in skin wounds; however, it decreases to a considerable extent. [ 218 ] As identified in silico and confirmed by luciferase reporter assay, RAC1 is a miR‐200b/c‐3p target. Forced miR‐200b/c‐3p expression repressed RAC1 and inhibited keratinocyte migration and re‐epithelialization in a mouse back skin full‐thickness wound healing model.…”