Elsevier

Medical Hypotheses

Volume 110, January 2018, Pages 64-67
Medical Hypotheses

Recently discovered interstitial cells “telocytes” as players in the pathogenesis of uterine leiomyomas

https://doi.org/10.1016/j.mehy.2017.11.003Get rights and content

Abstract

Uterine telocytes are interstitial cells characterized by a very long cytoplasmic prolongations, which form a 3D network, functionally integrating a wide variety of different cells. Leiomyomas (uterine fibroids) are benign tumors, which pose a huge threat concerning various health problems in women affected by this condition. The exact cause of leiomyomas development is, however, still largely unknown. Therefore, in an attempt to clarify their etiology, we performed an immunohistochemical characterization of telocytes in leiomyomas as well as in normal myometrium. Tissue samples of intramural leiomyomas from 26 women (age 46.26 ± 11.07) were immunohistochemically stained for the expression of c-kit (CD117) antigen, one of the markers of telocytes. C-kit (CD117) antigen is useful for a routine immunohistochemical identification of uterine telocytes in histological sections of myometrium. In normal, healthy myometrium the c-kit positive telocytes occupy approximately 2.2% of the area of a tissue slide, contrasting with no detectable c-kit positive cells within leiomyomas. As telocytes are thought to be key players in the regulation of tissue homoeostasis, our data suggest that uterine telocyte loss may have important implications in the pathogenesis of leiomyomas. In addition, we supposed to summarize three hypotheses on the association of the cells telocytes loss within the myometrium and formation of leiomyomas. These hypotheses include the loss of telocytes’ functions as “sex hormone sensors” and regulators of smooth muscle cells cycle; the role of telocytes as progenitor cells for the development of leiomyomas; and the hypothesis of decreased angiogenesis after telocytes’ loss with subsequent hypoxia (as a key factor for leiomyomas development).

Introduction

There have been a huge body of scientific works published recently, concerning a novel population of interstitial cells termed telocytes. These cells are characterized by very long cytoplasmic prolongations, which form a 3D network, structurally and functionally integrating immunologically active cells, smooth muscle cells, epithelial cells, nerve fibers and blood vessels. Often these cells are called just ”connecting cells“. This arrangement has been repeatedly found in essentially every organ of the human body including organs of the female reproductive system [1], [2]. Many studies describe the role of these cells not only in regulation of physiological functions, but also in plenty of pathological conditions, where the alteration of telocytes is regarded as one of the principal pathological changes. This disruption of normal telocytes physiology is commonly described in terms of their ultrastructure, quantitative changes and modification of their topographical relations with surrounding cells and extracellular components. Focusing on the female reproductive system, dysfunction of telocytes is associated with the pathogenesis of tubal infertility [3], [4], endometriosis [5], premature ovarian failure [6], or preeclampsia [7], [8]. Several works have been published recently, implying telocytes’ dysfunction as one of the key factors also in tumorigenesis [9], [10], [11]. Hence, the recent knowledge indicates, that telocytes represent a cardinal cell population with an irreplaceable role in tissue homeostasis and in cell proliferation, differentiation, and survival.

Leiomyomas (uterine fibroids, myomas) are benign monoclonal tumors, which originate from the muscle layer of the uterus (myometrium). Apart from the uncontrolled proliferation of smooth muscle cells, leiomyomas are also characterized by an increased susceptibility to endocrine stimuli and typical changes in the morphology of extracellular matrix (ECM), with disorganized architecture and alterations in the structure and production of various ECM components [12], [13]. Despite their benign nature, these tumors pose a huge threat concerning various health problems in women affected by this condition. The most severe complications associated with uterine fibroids are uterine bleeding, pelvic pain, infertility, miscarriage and a number of other pregnancy-associated complications [14], [15], [16]. Moreover, uterine leiomyomas are the most common tumors in women. According to Ahrendt et al. [17], in European population more than 40% of women over 30 years of age have suffered from leiomyomas and more than 50% of all women may develop leiomyomas at some time in their life. For all that, there is a high urgency to acquire a detailed insight into their etiology and pathogenesis.

Intense research of leiomyomas in recent years introduced a number of risk factors and possible causes. The exact cause is, however, still largely unknown. Therefore, in attempt to clarify their etiology, we performed an immunohistochemical characterization of telocytes within leiomyomas as well as in normal myometrium. We searched for an answer about the possible role of these recently described interstitial cells in the pathogenesis of uterine leiomyomas development.

Section snippets

Patients and methods

The specimens of uteruses were taken from 26 women (aged 19–69, mean age 46.26 ± 11.07) who underwent hysterectomy with diagnosis of leiomyomas. The study protocol was approved by the local ethical committee of the General Hospital in Komarno, Slovakia, and informed consent was obtained from every patient. All tissue samples were firstly examined by a pathologist and the diagnosis “intramural leiomyomas” was established. Five control samples of normal myometrium were obtained from the

Results

Among unstained smooth muscle cells of normal myometrium, telocytes’ cytoplasm showed strong c-kit (CD117) positivity, recognized by brown stain by using diaminobenzidine. The cell bodies of telocytes were spindle-shaped or star-shaped with visible beginnings (proximal portions) of their cytoplasmic projections (Fig. 1). Telocytes were present in all sublayers of myometrium and the average percentage of the positive area within the normal myometrium was 2.19 ± 0.51%. Surprisingly, inside

Discussion

Our study showed, that within the normal myometrium the c-kit positive telocytes occupy approximately 2% of the area of a tissue slide. The exact role of uterine telocytes is not clear, but most of the authors suppose their role in intercellular signaling, mechanical and chemical sensation (“hormone sensors”), bioelectrical signaling, modulation of myometrial contractility, or guidance of immune cells [18]. Based on our results, c-kit positive cells are not present within the uterine

Conflict of interest

We declare that, we have no conflict of interest.

Ethical approval

This study was approved by the local ethical committee of the General Hospital in Komárno, Slovakia. The patients provided written informed consent prior to participating in the study.

Acknowledgement

The authors thank Mrs. Gabriela Fujerikova for technical assistance during histological preparation.

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