TELOCYTES AND INNERVATION OF THE HUMAN BLADDER LAMINA PROPRIA AND THEIR ROLE IN THE AFFERENT INPUTS IN THE NEUROGENIC DETRUSOR OVERACTIVITY

INTRODUCTION AND AIM OF THE STUDY. In the human bladder, the integration and the transmission of the sensory perceptions would be entrusted to the urothelium and to some components of the lamina propria (LP) i.e. myofibroblats and nerve endings. The urothelium has the capability to survey and inform about the urine composition, the hydrostatic pressure and the wall distention, releasing chemical signals to the underlying LP (1). Recently, by using morphological techniques, we has been shown that the bladder LP holds telocytes (TC), intriguing stromal cells which roles and functions are still being defined. These cells have been found in all organs so far examined and always form a 3D network behaving as a scaffold for the connective components. Furthermore, TC might be involved in local signal transduction, as suggested by the presence of vesicles of exocytosis and exosomes. In the human bladder, the TC form a 3D network that, likely, is mixed with myofibroblasts. Bladder TC show different immune-phenotype accordingly to their location. In the upper LP (ULP), all the TC are PDGFR+ (a growth factor receptor); however, those located farther from the urothelium, also express SMA (a thin contractile filament protein). In the deeper part of the LP (DLP), which extends from the discontinuous muscolaris mucosae up to the detrusor, all the TC are only CD34+ (cluster of differentiation protein). The neurogenic detrusor overactivity (NDO) is a voiding disorder whose pathogenesis is under debate. Following the new acknowledges on the relevance of the local sensory system (urothelium plus LP) in the bladder physiology, the hypothesis that the NDO might be due, at least in part, to an incorrect handling of the afferent signals at urothelium and/or LP level has strengthened (2). The present work was aimed to investigate in the bladder LP of NDO patients whether the TC exhibited relevant changes and whether this potential changes could be correlated to the disease. MATERIALS AND METHODS. Full-thickness specimens of the bladder wall were collected from 8 NDO patients (4 females, 4 males; mean age: 40 ± 2.9 years) underwent to partial/total cystectomy. The patients were homogenous for etiology, length of the disease and clinical course. The choice of the surgery was taken on the basis of botulinum toxin and anti-muscarinic treatment inefficacy, of urodynamic parameters and of personal reasons. The control group was represented by full-thickness specimens of the bladder wall of six patients (1 females, 5 males; mean age: 72 ± 3 years) operated for bladder cancer. The local Ethical Committee approved the study protocol. The specimens were processed for histological and immunohistochemical studies. Image analysis and the appropriate statistics were performed. RESULTS. In all the NDO patients, the ULP was thicker than in controls and characterized by the presence of a consistent inflammation (Fig.1) that enlarge, but not interrupt, the TC net. The TC showed long and thin processes oriented parallel and perpendicular to the bladder surface, frequently coupled to plasma cells. Underneath the urothelium, the continuous monolayer of TC PDGFRα+ was intact in all the patients. However, the number of the PDGFR+/SMA+ TC as well as their percentage respect to the total TC significantly increased in NDO patients (Fig.1) together with an increase in Cav1 labeling (a protein of the caveolae). In the DLP of NDO patients, the TC CD34+ net was preserved, but the cells show a larger size. Quantitation of the CD34+ structures displays a significant increase of the CD34 labeling. INTERPRETATION OF RESULTS. The increase in αSMA expression and caveolae of TC in the ULP as well as the enlarged body of TC in the DLP can be interpreted as signs of cell activation, reasonably aimed at the maintaining of the scaffold integrity along the entire bladder wall. However, the constant thickening of the LP in the NDO patients and the lack of a significant increase in cell number cause the augmentation of the dimension of the net mashes and consequently of the intercellular distances. This latter, in turn, would affect the functional integrity. Farther, the high frequency cell to cell contact between TC and plasma cells indicate a preferential communication of TC with the immunity system. It supports a TC role in immune-regulation and immune-surveillance and could be related to the loss of botulinum toxin efficacy. CONCLUSIONS. In summary, the TC of the LP show important immunohistochemical and structural changes compared to controls. These changes indicate a functional TC activation within the entire LP. Therefore, it can be concluded that all the TC are able to resist and adapt to this pathological condition. REFERENCES 1. Andersson KE, McCloskey KD. Lamina propria: the functional center of the bladder? Neurourol Urodyn. 2014. 2. Chapple C. Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder". Neurourol Urodyn. 2014.