Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism

International audienceExperimental Approach: Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids. Cultured organoids were exposed to 10 and 50 mU·mL−1 of thrombin, in the presence or not of protease‐activated receptor (PAR) antagonists. Organoid morphology, metabolism, proliferation and apoptosis were followed.Key Results: Thrombin favoured organoid maturation leading to a decreased number of immature cystic structures and a concomitant increased number of larger structures releasing cell debris and apoptotic cells. The size of budding structures, metabolic activity and proliferation were significantly reduced in organoid cultures exposed to thrombin, while apoptosis was dramatically increased. Both PAR1 and PAR4 antagonists inhibited apoptosis regardless of thrombin doses. Thrombin‐induced inhibition of proliferation and metabolic activity were reversed by PAR4 antagonist for thrombin's lowest dose and by PAR1 antagonist for thrombin's highest dose.Conclusions and Implications: Overall, our data suggest that the presence of thrombin in the vicinity of human colon epithelial cells favours their maturation at the expense of their regenerative capacities. Our data point to thrombin and its two receptors PAR1 and PAR4 as potential molecular targets for epithelial repair therapies

Can we define and characterize the aging lower urinary tract?—ICI-RS 2015

© 2017 Wiley Periodicals, Inc. The prevalence of lower urinary tract (LUT) symptoms increases with age but the etiology is unknown. This article aims to identify research directions that clarify the basis of this association. The initial question is whether biological age is the variable of interest or a time-dependent accumulation of factors that impact on LUT function at rates that differ between individuals. In particular, the accumulation of conditions or agents due to inflammatory states or tissue ischemia is important. Much of the above has been concerned with changes to bladder function and morphology. However, the outflow tract function is also affected, in particular changes to the function of external sphincter skeletal muscle and associated sacral motor nerve control. Nocturia is a cardinal symptom of LUT dysfunction and is more prevalent with aging. Urine production is determined by diurnal changes to the production of certain hormones as well as arterial blood pressure and such diurnal rhythms are blunted in subjects with nocturia, but the causal links remain to be elucidated. Changes to the central nervous control of LUT function with age are also increasingly recognized, whether in mid-brain/brainstem regions that directly affect LUT function or in higher centers that determine psycho-social and emotional factors impinging on the LUT. In particular, the linkage between increasing white matter hyperintensities and LUT dysfunction during aging is recognized but not understood. Overall, a more rational approach is being developed to link LUT dysfunction with factors that accumulate with age, however, the precise causal pathways remain to be characterized. Neurourol. Urodynam. 36:854–858, 2017. © 2017 Wiley Periodicals, Inc

Modifications fonctionnelles et pharmacologiques de l'appareil urinaire au cours du vieillissement chez le rat

L'OBJECTIF DE CE TRAVAIL A ETE D'EVALUER LES CONSEQUENCES DU VIEILLISSEMENT SUR L'APPAREIL URINAIRE CHEZ LE RAT MALE ET FEMELLE PAR DES APPROCHES CYSTOMANOMETRIQUES, PHARMACOLOGIQUES, HISTOLOGIQUES ET GENOMIQUES. L'ENSEMBLE DE CE TRAVAIL EXPERIMENTAL MONTRE QUE LE VIEILLISSEMENT DE L'APPAREIL URINAIRE CHEZ LE RAT EST CARACTERISE PAR DES MODIFICATIONS DES FONCTIONS VESICALES ET URETRALES, SOUVENT SEMBLABLES CHEZ LE MALE ET LA FEMELLE. EN PARTICULIER, DES INSTABILITES VESICALES ET UN RETARD A LA RELAXATION URETRALE ONT ETE OBSERVES. CES MODIFICATIONS FONCTIONNELLES SONT ASSOCIEES A DES ALTERATIONS HISTOLOGIQUES ET PHARMACOLOGIQUES DIFFERENTES SELON LES NIVEAUX DE L'APPAREIL URINAIRE : LE DOME VESICAL, LA BASE DE VESSIE ET L'URETRE. AU NIVEAU TISSULAIRE, UNE INFILTRATION DE COLLAGENE A ETE SPECIFIQUEMENT LOCALISEE AU NIVEAU DE LA BASE VESICALE, A L'EXCLUSION DU DOME. LES REPONSES FONCTIONNELLES OBTENUES DANS LES DIFFERENTS TISSUS SUGGERENT DES MODIFICATIONS DANS LES NEUROTRANSMISSIONS ADRENERGIQUE, CHOLINERGIQUE ET NANC. LES MODIFICATIONS DE L'EXPRESSION DES GENES AU COURS DU VIEILLISSEMENT VESICAL SUGGERENT QU'UN NOMBRE LIMITE DE PROTEINES, DONT LE FACTEUR DE CROISSANCE NGF, EST IMPLIQUE DANS LES MECANISMES DE LA SENESCENCE. CES RESULTATS MONTRENT QUE LE VIEILLISSEMENT EST RESPONSABLE D'UNE ALTERATION DE LA COORDINATION URETRO-VESICALE ABOUTISSANT A DES MODIFICATIONS SIMILAIRES A CELLES QUI SONT PRESENTES DANS LES PATHOLOGIES OBSTRUCTIVES. LE RAT AGE SEMBLE ETRE UN MODELE EXPERIMENTAL D'INTERET POUR UNE MEILLEURE COMPREHENSION DES MECANISMES DU VIEILLISSEMENT DE L'APPAREIL URINAIRE ET DE SES CONSEQUENCES. AINSI, DE NOUVELLES APPROCHES THERAPEUTIQUES, EN PARTICULIER POUR LE TRAITEMENT DE L'INCONTINENCE URINAIRE, POURRAIENT ETRE PROPOSEES.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Explorations fonctionnelles de la fonction vésicale chez la souris (études urodynamiques, pharmacologiques et génétiques)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF