Recently discovered interstitial cells “telocytes” as players in the pathogenesis of uterine leiomyomas
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.
References (41)
- et al.
A putative role for telocytes in placental barrier impairment during preeclampsia
Med Hypotheses
(2015) - et al.
The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus
Gynecol Oncol
(2003) - et al.
Telocytes in female reproductive system (human and animal)
J Cell Mol Med
(2016) - et al.
Telocytes in the reproductive organs: current understanding and future challenges
Sem Cell Dev Biol
(2016) - et al.
Tubal telocytes: factor infertility reason?
Folia Med Cracov
(2016) - et al.
Time-dependent disruption of oviduct pacemaker cells by Chlamydia infection in mice
Biol Reprod
(2010) - et al.
Immunohistochemical alterations of Cajal-like type of tubal interstitial cells in women with endometriosis and tubal ectopic pregnancy
Arch Gynecol Obstet
(2013) - et al.
Telocytes as potential targets in a cyclophosphamide-induced animal model of premature ovarian failure
Mol Med Rep
(2016) - et al.
Placental hypoxia developed during preeclampsia induces telocytes apoptosis in chorionic villi affecting the maternal-fetus metabolic exchange
Curr Stem Cell Res Ther
(2016) - et al.
Infrastructure of the telocytes from tumor stroma in the skin basal and squamous cell carcinomas
Rom J Morphol Embryol
(2013)
Immunohistochemical characterization and functional identification of mammary gland telocytes in the self-assembly of reconstituted breast cancer tissue in vitro
J Cell Mol Med
Particular molecular and ultrastructural aspects in invasive mammary carcinoma
Rom J Morphol Embryol
Uterine fibroids
N Engl J Med
Uterine fibroid: common features of widespread tumor (Review article)
Folia Med Cracov
Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations
Hum Reprod Update
Spontaneous rupture of infarcted leiomyoma into endometrial cavity in a perimenopausal woman
Arch Gynecol Obstet
Pregnancy outcomes in oocyte recipients with fibroids not impinging uterine cavity
Arch Gynecol Obstet
Prevalence of uterine myomas in women in Germany: data of an epidemiological study
Arch Gynecol Obstet
Uterine telocytes: a review of current knowledge
Biol Reprod
Uterine leiomyoma and telocytes: impact on pathogenesis?
EC Gynaecology
Cited by (18)
Telocytes in Cutaneous Biology: A Reappraisal
2023, Actas Dermo-SifiliograficasRoles and distribution of telocytes in tissue organization in health and disease
2021, Tissue Barriers in Disease, Injury and RegenerationTerminologia Histologica 10 years on: some disputable terms in need of discussion and recent developments
2019, Annals of AnatomyCitation Excerpt :As of July 2019, more than 380 articles are being displayed in MEDLINE/PubMed after “telocytes” OR “interstitial Cajal-like cells” are searched for. From the functional perspective, telocytes were reported to play an important role in regeneration, tissue repair and angiogenesis (Vannucchi et al., 2016; Yang and Xiao, 2016; Shoshkes-Carmel et al., 2018; Hussein and Mokhtar, 2018), but also in the pathogenesis of a vast spectrum of diseases (Ibba-Manneschi et al., 2016; Pasternak et al., 2016; Varga et al., 2018b, 2019a). Despite this immense extent of emerging knowledge, telocytes still have not been widely accepted among researchers as a stand-alone cell population.
Immunohistochemical and ultrastructural evidence for telocytes in the different physiological stages of the female rat mammary gland
2019, Life SciencesCitation Excerpt :Taken together the previous suggestions and the immunohistochemical findings of this study, it could be assumed that TCs might play a critical role controlling the structural and functional remodeling from one stage to the other either by the proliferation during the preparation of the gland for lactation or controlling apoptosis during the involution of the gland after weaning. Owing that to the specific roles of TCs in cell signaling, tissue homeostasis, remodeling and angiogenesis which proved by Zheng et al., [36] and Varga et al., [38]. Thus TCs were seen as future targets with implications for regenerative medicine [39].
What podoplanin tells us about cells with telopodes
2018, Annals of AnatomyCitation Excerpt :Therefore expression of podoplanin in TCs needs further testing, with double-labelling studies using CD34 as second marker being strongly recommended. It was recently hypothesized that uterine TCs loss could be important in the pathogenesis of leiomyomas (Varga et al., 2018). That hypothesis resulted after a comparative study of CD117/c-kit expression in normal myometrium and intramural leiomyoma (Varga et al., 2018).
Histological study of telocytes in mice intrauterine adhesion model and their positive effect on mesenchymal stem cells in vitro
2024, Cell Biology International