From their initial description in 2005 to this day, telocytes (TCs) have been described in the ovary, uterine tubes, uterus, vagina, mammary gland, and placenta. Their morphological features, immunophenotype, physiological functions, and roles in disease have been thoroughly documented in both animal models and human subjects. TCs, with their extremely long cytoplasmic processes called telopodes, play a pivotal role in the morphological and functional interconnection of all the components of the interstitial compartment, but also with constituents of the parenchyma. Although there is no specific immunohistochemical marker for their identification, the most cited are CD 117, CD 34, platelet-derived growth factor receptor (PDGFR), vimentin, and specific markers typical for the female reproductive system (FRS)—estrogen and progesterone receptors (ER and PR). This immunophenotype provides important clues to their physiological roles. Their main functions include the regulation of hormone-dependent processes, intercellular signaling, immune surveillance, microenvironmental maintenance, and the nursing of stem cells. In a situation where TCs are functionally or morphologically decimated, many disease entities may develop, including premature ovarian failure, endometriosis, ectopic pregnancy, infertility, preeclampsia, or even breast cancer. The common denominator of many of these conditions is that their etiopathogenesis is either partially known or completely obscure. Even though the exact role of TCs in these conditions is yet to be revealed, multiple lines of research indicate that their future clinical application may enrich diagnostic-therapeutic strategies of countless conditions. TCs are also heavily debated in terms of their possible use in regenerative medicine and tissue engineering. Some of the concepts related to TC research are strongly substantiated by experimental data, while others are highly speculative. Only future research endeavors will clearly distinguish dead-end lines of research from genuine contributions to the field.

The invention of such state-of-the art microscopic techniques like atomic force microscopy with a resolution of fractions of a nanometer, and the overall current level of knowledge in morphological disciplines have brought about a widespread impression, that identifying a new cell population in the 21st century is highly unlikely [...]

Despite recent advancements in reproductive medicine, recurrent implantation failure and habitual abortion remain ongoing issues. One of the most important aspects of successful implantation is the intricate immune response and regulation necessary for the acceptance of the hemiallogenic embryo. The most numerous immune cells in the decidua are uterine natural killer cells (uNK). Studies suggest that changes in the uNK count and physiology may be responsible for the aforementioned pathological conditions. Thus, testing for uNK may provide valuable insights into their pathogenesis. The study compared Pipelle endometrial sampling with conventional curettage to find out whether the less invasive Pipelle method is a viable alternative of tissue collection. Tissue samples from 14 patients obtained by both methods were examined. The average size of tissue samples obtained with Pipelle was 17 mm2, samples obtained with curettage had on average 34 mm2. Using immunohistochemical visualization of CD56 (NK cells) and granzyme B antigens (serine protease-expressing activation state of NK cells), it was found that the average total count of CD56 / mm2 was 115 for Pipelle and 120 for curettage, respectively. The study also proved a correlation between granzyme B positivity and identification of NK cells clusters. The results indicated that Pipelle endometrial sampling seems a suitable method of tissue harvesting for the purpose of uNK cells examination. Pipelle endometrial sampling is safe, cost-effective and can be performed on an outpatient basis without the need of anesthesia or analgesia. Several issues remain yet to be solved: how to standardize the subsequent uNK testing, how to interpret the results and finally yet importantly, how to use this knowledge in personalized treatment protocols.

Infertility affects approximately 48 million couples globally. Despite the enormous progress of the methods of reproductive medicine that has been made since the first test-tube baby was born in 1978, the implantation rate of day-3 embryos is only around 15-20 % and 30 % of day-5 embryos. Numerous strategies aim to improve implantation rates and prevent repeated implantation failure. However, there is no specific general recommendation leading to satisfying results. One of the many risk factors relevant in this regard is the uterine immunological make-up, mainly the uterine Natural Killer (uNK) cells. They orchestrate the overall immune response during implantation by influencing trophoblast invasion and vascular remodeling and throughout pregnancy, uNK cells are also the main immune cells at the maternal–fetal interface. Previously, uNK count has been correlated with various fertility issues including idiopathic recurrent miscarriage. The present study used endometrial samples collected from 256 patients with recurrent implantation failure (RIF), habitual abortion (HA) and idiopathic sterility. Samples were collected between day 19 and 21 of the menstrual cycle mainly by Pipelle endometrial sampling. The samples were fixed in formalin for 24 hours and further processed for immunohistochemistry using anti-CD56 to visualize this antigen marker of uNK cells. Immunohistochemical counting was performed to assess the low, normal, or elevated count of uNK cells. According to the one-way ANOVA test, the age of our patients did not have any influence on the count of uNK cells. With Spearman correlation analysis, we found statistically significant correlation (p-value 0.05) of -0.133 between prior miscarriage and lower uNK cell count. Using the same analysis we found statistically significant correlation (correlation 0.233 with p value 0.01) between number of uNK cells and activation status. Patients with higher uNK cells were more frequenty diagnosed with endometriosis (p-value 0.05, correlation 0.130). Patients with an immunological factor of sterility (defined by a clinical immunologist) had a lower chance of gravidity (-0.203 with p-value 0.01). Based on our results, we can confirm that there is a correlation between RIF, HA, idiopathic sterility, endometriosis, and immunological factor of sterility (uNK cell count). The true predictive value with regard to fertility outcomes needs to be addressed in future research.

Reproductive immunology is at the forefront of research interests, aiming to better understand the mechanisms of immune regulation during gestation. The relationship between the immune system and the implanting embryo is profound because the embryo is semi-allogenic but not targeted by the maternal immune system, as expected in graft-versus-host reactions. The most prominent cell population at the maternal–fetal interface is the population of uterine natural killer (uNK) cells. Uterine NK cells are two-faced immunologically active cells, bearing comparison with Janus, the ancient Roman god of beginnings and endings. Their first face can be seen as natural killer cells, namely lymphocytes, which are critical for host defense against viruses and tumors. Even though uNK cells contain cytolytic molecules, their cytotoxic effect is not applied to classical target cells in vivo, playing a permissive rather than a defensive role. Their second face is crucial in maintaining physiological gestation—uNK cells show critical immunomodulatory functions with the potential to control embryo implantation and trophoblast invasion, regulate placental vascular remodeling, and promote embryonic/fetal growth. Therefore, we believe that their current designation “natural killer cells” (the first “cytotoxic” Janus’s face) is misleading and inappropriate, considering their principal function is supporting and maintaining pregnancy. In this narrative review, we will focus on three lesser-known areas of knowledge about uNK cells. First, from the point of view of histology, we will comprehensively map the history of the discovery of these cells, as well as the current histological possibilities of their identification within the endometrium. To be brief, the discovery of uNK cells is generally attributed to Herwig Hamperl, one of the most influential and prominent representatives of German pathology in the 20th century, and his co-worker, Gisela Hellweg. Secondly, we will discuss the interesting aspect of terminology, since uNK cells are probably one of the human cells with the highest number of synonymous names, leading to significant discrepancies in their descriptions in scientific literature. From the first description of this cell type, they were referred to as endometrial granulocytes, granular endometrial stromal cells, or large granular lymphocytes until the end of the 1980s and the beginning of the 1990s of the last century, when the first publications appeared where the name “uterine NK cells” was used. The third area of present review is medical teaching of histology and clinical embryology. We can confirm that uNK cells are, in most textbooks, overlooked and almost forgotten cells despite their enormous importance. In the present narrative review, we summarize the lesser-known historical and terminological facts about uNK cells. We can state that within the textbooks of histology and embryology, this important cell population is still “overlooked and neglected” and is not given the same importance as in fields of clinical research and clinical practice.