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Fonction des rétinoïdes dans les membranes foetales humaines. Action pro-cicatrisante médiée par LOXL4.

Abstract : Vitamin A and its active derivates (retinoids) are essential molecules for life from the embryonic development to the adulthood. Because of these numerous functions and especially because of their pro-healing properties, they are commonly used in clinic in dermatology and ophthalmology in particular. Despite this routine clinical use, the molecular and cellular mechanisms used by retinoids to promote a healing process remain unclear. To better understand these mechanisms, but also to expand its clinical use to the premature rupture of fetal membranes (PROM), we looked to pro-healing properties of atRA (active derivative of vitamin A) on the human fetal membranes. While amnion and chorion are unable to initiate a physiological process of healing after injury, our results demonstrate a positive effect of atRA on the migration of primary amniocytes, leading to an healing improvement of up to 80% in vitro. This work, completed by a transcriptomic analysis performed on fetal membranes and primary amniocytes treated or not with atRA, allowed the identification of many genes regulated by atRA within the amnion and the amniocytes. Among these genes, we looked to a member of the lysyl oxidase family, LOXL4, which plays a key role in the dynamic of the extracellular matrix by regulating collagen crosslinking. First, transcription and promotology experiments have shown that atRA strongly induced the expression of LOXL4 in a direct manner. Then, the inhibition of the LOXL4 protein in scratch assay experiments (using β-aminopropionitrile or a specific siRNA) allowed us to demonstrate that the pro-healing effect of atRA was mediated, at least in part, by the retinoid-induction of this gene. Besides providing new elements to understand how atRA exerts their pro-healing properties, this work proposes atRA as a promising candidate to improve the clinical management of premature rupture of the fetal membranes by promoting re-epithelialization of the amnion.
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Marion Rouzaire. Fonction des rétinoïdes dans les membranes foetales humaines. Action pro-cicatrisante médiée par LOXL4.. Médecine humaine et pathologie. Université d'Auvergne - Clermont-Ferrand I, 2016. Français. ⟨NNT : 2016CLF1MM18⟩. ⟨tel-01845749⟩

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