Exam (elaborations)
Exam Question on wound healing
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- Liverpool John Moores University (LJMU)
Exam question and answer of microRNAs, keratinocytes and wound healing. Answer and references included
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6) Discuss microRNAs and their contributions to keratinocyte migration during cutaneous woundhealing.
Micro RNAs (miRNA) are small single stranded non-coding RNA molecules which were originally
thought to have no function. It is now known that miRNAs are important components of our
biochemistry. Regarding wound healing, many miRNAs have been determined as part of the complex
pathways involved. Specifically, miR-21-5p has been researched in relation to keratinocyte
migration.
Immediately after injury occurs vasoconstriction reduces the excessive loss of blood. This triggers
the release of cytokines, growth factors and pro-inflammatory mediators. The main growth factors
released by platelets are platelet derived growth factor (PDGF) and transforming growth factor-beta
(TGF-β). The purpose of TGF-β & PDGF is to stimulate a response from the matrix to produce cells for
the preparation of rapid deposition of new connective tissue to begin rebuilding the extracellular
matrix (ECM). After 3 days wound cleansing is taken over by monocytes which become activated
and become wound macrophages. These macrophages are responsible for the release of TGF-β &
PDGF. Due to the loss of blood flow and therefore oxygen supply, the hypoxic wound environment
triggers the release of vascular endothelial growth factor (VEGF) basic fibroblast factor (bFF) and
transforming growth factor – β (TGF-β). TGF-β is said to post transcriptionally increase miR-21
activity through Smad 1 (Carboxy-terminal MH2 domain of SMAD1) interactions with RNA helicase
p68 – a crucial component of DROSHA (Davis et al, 2008). Drosha is a Class 2 ribonuclease III enzyme
executes the initiation step of miRNA processing in the nucleus. When inhibited primary-miRNA are
formed but not premature or mature miRNA.
MiR-21 has been shown to dramatically enhance keratinocyte migration by the research conducted
by Yang et al (2011). Through the treatment of HaCaT, a human keratinocyte cell line, with TGF-β1
they were able to show that miR-21 expression was dramatically increased at 6 hours after
treatment indicating the interaction between TGF-β and miR-21. They also used techniques such as
PCR to prove that miR-21 was implicitly involved in the mechanism of action of tissue inhibitor of
metalloproteinase-3 (TIMP3) and T-lymphoma invasion and metastasis inducing protein (TIAM-1).
These targets if miR-21 have been researched previously in relation to cancer metastasise (Asangani
et al, 2008).
MiRNA 205 has also been implicated in the aid of cellular migration, some research shows it can aid
keratinocyte migration but there is conflicting evidence, which is unlike miR-21 as the common
theme throughout all research whether it was wound healing or cancer metastasis, they all stated
miR-21 aided the migration. Yu et al (2010) investigated how miR-205 effected keratinocyte
migration. They found that miR-205 activity resulted in F-actin alterations and decreased cell-
substrate adhesions, they also found that miR-205 inhibited the Src homology 2 domain containing
inositol 5-phosphatase (SHIP 2). However conflicting research by Wang et al (2016) investigated
inhibition of miR-205 in topical wound sites on mice with the application of a single 60μl application
of 5μM antagomir-205. Real-time PCR was used to quantify the knockdown of miR-205 in the
antagomir treated wounds, they found a continuous reduction in miR-205, they concluded that the
knockdown of miR-205 can promote keratinocyte migration in both in vitro and in vivo models.
To conclude, it is clear the miRNAs are involved in the migration of keratinocytes in wound healing
situations. Clear research has been published giving evidence to support that miR-21 is implicitly
involved in the keratinocyte migration however, the evidence to support or deny miR-205
involvement in keratinocyte migration is yet to be determined. The conflicting research shows that
further research is necessary to determine the molecular function of miRNAs and their involvement
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