Editors' ChoicePhysiology

The Healing Switch

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Sci. Signal.  19 Mar 2013:
Vol. 6, Issue 267, pp. ec66
DOI: 10.1126/scisignal.2004150

Wound healing is a regenerative process that is tightly controlled by cytokines and growth factors, including transforming growth factor–β (TGF-β), and microRNAs (miRNAs). Sundaram et al. showed that the posttranscriptional inverse regulation of follistatin 1 (FSTL1) and miR-198, which is encoded within the FSTL1 transcript, was a critical switch for wound healing. Expression profiles and protein gradients in healthy or wounded human skin organ cultures revealed that FSTL1 was abundant in wounded skin but not healthy skin, whereas the miR-198 abundance was less in wounded skin compared with healthy skin. Keratinocyte monolayers transfected with siRNA against FSTL1 failed to migrate into the space made by scratching the monolayer, suggesting that FSTL1 promotes keratinocyte migration during wound healing. Overexpression of miR-198 in these cultures substantially suppressed migration without affecting the abundance of FSTL1, suggesting that this effect of miR-198 was not due to targeting FSTL1 transcripts. Gene expression profiles of cultured keratinocytes and human skin organ cultures after wounding in the presence or absence of exogenously added miR-198 revealed potential targets of miR-198, including PLAU (encoding urokinase-type plasminogen activator), DIAPH1 (encoding diaphanous homolog 1), and LAMC2 (encoding laminin γ2 chain), genes that each contain at least one binding site for miR-198. Knockdown of PLAU, DIAPH1, or LAMC2 suppressed keratinocyte migration, and their abundance was inversely correlated with that of miR-198 in the cutaneous wound models. Using mutant and recombinant proteins and RNA interference, Sundaram et al. showed that KSRP (KH-type splicing regulatory protein) bound a GUG motif of pre-miR-198 in the 3′-UTR of the FSTL1 transcript to promote processing to mature miR-198. TGF-β1, but not other growth factors, reduced the abundance of KSRP, possibly by stimulating the production of miR-181a. TGF-β1 and miR-181a were abundant in wounded tissue, whereas KSRP was not. Furthermore, the abundance of PLAU, DIAPH1, LAMC2, FSTL1, and TGF-β1 was absent or substantially decreased in chronic nonhealing ulcer wounds from patients with diabetes mellitus, whereas miR-198 and KSRP were abundant, suggesting that this healing switch is dysfunctional in chronic wounds.

G. M. Sundaram, J. E. A. Common, F. E. Gopal, S. Srikanta, K. Lakshman, D. P. Lunny, T. C. Lim, V. Tanavde, E. B. Lane, P. Sampath, ‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature 495, 103–106 (2013). [PubMed]

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