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Title:
The role of interstitial cajal-like cells (telocytes) in the pathogenesis of uterine fibroids
Author:
Subject:
uterine fibroids ; telocytes ; CD34 ; angiogenesis ; nerve fibers
Abstract:
The first mention about uterine fibroids dates back to the time of Hippocrates. However, there are stili wide gaps in the understanding of their pathogenesis. No single theory explains the background of the oldest uterine pathology, which affects more than 50% of women worldwide. By contrast, a newly depicted cell type called telocyte was only recently identified in the past twenty years. The unique features of telocytes coupled with experimental evidence from numerous studies lead us to create new hypotheses of the uterine fibroid pathogenesis. The results of current research will be discussed in our thesis. We explored the important telocytes interactions in the context of the uterine fibroid architecture. Telocytes not only internet with a variety of histological structures but have been the first line cells respond to hypoxia, thereby attracting our attention. The aim of the study was to identify uterine telocytes in the foci of fibroids and elucidate their role in fibrosis development, loca] angiogenesis, and autonomie nerves interplay. Firstly, we performed the primary identification of telocytes using immunolabelling with further markers: c-kit, CD34, PDGFRa, tryptase. Jmmunofluorescent labeling was also used for all samples: the corpus and uterine cervix (exo- and endocervix) as well as leiomyoma foci. The use of mast cell tryptase staining enabled c-kit-positive mast c ; ells to be distinguished from c-kit-positive TCs. TCs were considered cells that were c-kit positive and tryptase negative concurrently with the characteristic morphology in tissue samples. Additionally, cells double positive for CD34 and PDGFRa with characteristic morphology and localization were also recognized as TCs. We also intended to grossly evaluate the structure of the fibroid, comparing collagen and muscle components in the foci of fibroids as well as in unchanged myometrium using hematoxylin and eosin and Masson 's tri chrome stainings. The performed study revealed the existence of uterine telocytes in all observed uterine tissues (fibroids, unchanged myometrium from the corpus of the uterus and uterine cervix) mostly located in close vicinity of blood vessels, between muscle fibers. Our next step was to focus attention on the interaction between uterine telocytes and autonomie innervation. Neuronal struetures were identified by immunolabeling for neuronal markers: protein gene product PGP 9.5, indueible nitrie oxide synthase (i OS), eholine aeetyltransferase (ChAT), and tyrosine hydroxylase (TH). For the primary identifieation of teloeytes we perfonned the same immunostaining as mentioned above. The gross organization of myometrial tissue has been analyzed by routine histology as well. The autonomie innervation in the foei of fibroids was mainly eharaeterized by an ; increase in the number of iNOS and ChATimmunopositive neurons. Uterine teloeytes are also loeated elose to nerve fibers, emphasized their putative interplay with neuronal elements. The close vicinity of TCs with nerve endings eonfinned the unique involvement of these cells in neuronal regulation in the uterus; however, the role of the cellcell interaction with nerve fibers needs further explanation. The next issue we explored in the context of the pathogenesis of uterine fibroid was a linkage between telocytes and angiogenesis processes. Based on literature data telocytes arc eharaeterized by high sensitivity to hypoxia (more likely than fibroblasts). We picked up two additional specifie markers for vessels formation (CD3 l and sFlt-1 (anti-angiogenic factor)), and combine with immunostaining specific for TCs used before in order to reveal the correlation of telocytes with the expression of angiogenic markers. The declined number of CD34+/PDGFRa+-cells in leiomyoma was accompanied by a prevalence of collagen deposits, poor vascularization, a high immunopositivity of the myometrium to sflt-1 (anti-angiogenic factor). We concluded that uterine telocytes, sensitive for angiogenic factors (PDGF and VEGF) and ischemia, have been declined and even disappeared during fibrosis and are mainly located in close vicinity of blood vessels. They might play a role in the angiogenic response t ; o hypoxia, universal for the whole human body. The variety of heterocellular eontaets between telocytes and surrounding eells/anatomical structures in uterine fibroids allows us to Focus our attention on its importance. Each leiomyoma is aecompanied by hypoxia process, exceeded production of extracellular matrix and formation of "vascular capsule". Concluding, the loca! declining of telocytes in fibroids also reflects its sensitivity to hypoxia and indirect involvement in basie processes leading to fibrosis. In addition, the reduced density of uterine telocytes eorrelates with an elevated number ofNOS-positive neurons. Uterine telocytes are present in all parts of the human uterus, close to blood vessels, nerves, between smooth muscle cells and also in the capsule of the fibroid. Connection points in the pathophysiology of uterine fibroid and properties of telocytes allow us to underline the importanee of telocytes in the pathogenesis of uterine fibroids.