The uterus is a functionally unique organ. It is capable of contractions of varying intensity - weak contractions to shed the endometrial lining during menstrual bleeding and strong contractions during labor. The elasticity of its smooth muscle cells also allows the uterus to significantly grow in size and volume during pregnancy and to retract to almost original size afterwards. While the hormonal and biochemical interactions are largely understood, some aspects - organ wide coordination of muscle cells, outside interference to modulate these contractions - still remain unclear [11].

TCs were first identified in the uterus in 2005 [12]. They were identified in the endometrial stroma of the stratum functionalis, as well as in the basal endometrium after menstruation [13]. TCs were observed to follow the shape of the neighboring epithelial architecture. Given their location and what is known about their capabilities, it’s possible they provide structural support for endometrial glands, forming a functional unit [13]. Endometrial TCs express connexin 43, a gap junction protein which is linked with maturation of decidua and the decrease of which is connected with recurrent pregnancy loss [14].

TCs were also identified in myometrium of both pregnant and non-pregnant women, forming a 3D supportive network [15]. Numerous extracellular vesicles (EVs) were observed, suggesting an active role of TCs in this location. Interestingly, no significant differences in EVs released from TCs in pregnant or non-pregnant myometrium were observed [16]. Immature uteri contain only a small number of TCs when compared to adult, non-pregnant uteri. Pregnant uteri show a further increase in endometrial TCs and a significant decrease in myometrial TCs. The telopodes of TCs of a pregnant uterus were shorter and thicker when compared to telopodes of samples from non-pregnant uteri. The highest count of myometrial TCs was observed in postpartum uteri [17]. These observations further support the functional importance of uterine TCs, enabling us to hypothesize that the concentration of TCs is in direct correlation with the contractibility of the uterus. This thesis was further supported by demonstration of the presence of small-conductance calcium-activated potassium channels in the TCs of non-pregnant myometrium, in contrast to their absence in the TCs of pregnant myometrium [18]. These channels were shown to participate in myometrial relaxation in vitro [19].

If we accept the possibility of a TCs network functioning as a “primitive nervous system”, we might be a step closer to defining the functional aspect of a pacemaker of uterine contractions. An inward hyperpolarizing current with a Ca²⁺ dependent component was observed in TCs from human non-pregnant myometrium, which also suggest their involvement in the excitability of myometrium [16]. It was also confirmed that TCs stain positive for the presence of estrogen receptor α and progesterone receptor A, intensely on the nuclear level and weaker in the cytoplasm [20]. A recent study also discovered a higher number of TCs in uterine leiomyomas in comparison to adjacent and even normal (distant) myometrium. TCs isolated in leiomyomas were showing signs of increased cellular activity - elongated telopodes, a large number of mitochondria and dilated endoplasmic reticulum cisternae, which would indicate their active role in the creation or growth of leiomyomas [21].

TCs were identified in fallopian tubes, predominantly in the lamina propria and in between smooth muscular fibres of the tunica muscularis externa. The concentration of TCs in the wall of the fallopian tubes decreases from the subepithelial area to the serosa. In contrast to TCs in the uterus, local TCs showed positivity to α-smooth muscle actin. TCs located in the fallopian tube tissue are positive for the presence of estrogen receptor α and progesterone receptor A on the TCs, even at the nuclear level [20]. Several disorders connected to damage or dysfunction of the fallopian tubes are also characterized by a reduction or complete loss of TCs.

Yang et al. observed in an animal model a significant reduction or complete loss of TCs in fallopian tubes with acute salpingitis. Remaining TCs were also damaged, with ultrastructural abnormalities, such as loss of organelles, swollen nucleus, mitochondria and endoplasmic reticulum dilatation, dissolution of telopodes, and loss of intracellular junctions [22].

A complete loss of TCs in fallopian tubes was also observed in an animal experiment, in which mice were infected with Chlamydia muridarum. This led to tubal dysfunction, due to a blocking of the propulsive contractions needed for egg transportation. The experiment also showed that it was not the effect of the infection that led to the disruption of TCs, but the upregulation of nitric oxide synthase 2, as part of the inflammatory response [23].

A very similar observation was made with fallopian tubes affected by endometriosis. Again, a reduction or complete disappearance of TCs was observed, along with signs of ultrastructural damage in the persisting TCs [24]. A reduction of the numbers of TCs or impairment of their functions may very well be a factor in infertility.

TCs in ovaries have not attracted much attention yet. Save for two animal experiments, there are no available papers on this topic. Liu et al., however, did prove the presence of TCs in ovarian stromal tissue and also made an interesting discovery. When they induced premature ovarian failure using cyclophosphamide, they also observed a significant reduction in the number of TCs in the ovarian tissue [25]. It is, of course, not yet clear if the reduction in the number of TCs is just a byproduct of generalized atrophy of ovarian tissue (and a possible marker of this disorder), or if ovarian function is actually dependent of their presence.

Abd-Elkareem et al. confirmed the presence of progesterone receptor A on ovarian TCs using immunostaining, with moderate cytoplasmic and negative nuclear activity. His experiment also showed that progesterone receptor A, while not exclusively located only on TCs, is vital for normal follicular development, ovulation, luteinization, and the formation and maintenance of the corpus luteum [26].

TCs in mammary gland were first mentioned in 2005 (then called interstitial Cajal-like cells). They were found in the stroma of the gland, in contact with plasma cells, lymphocytes, fibroblasts, mast cells, and macrophages [27]. It is well documented that mammary stroma having TCs play an important role in breast homeostasis [28]. In case of this specific organ, research is attempting to identify the role of TCs in cancerogenesis, in accordance with tissue organization field theory. According to this theory, the reasons for the creation of cancer are disorders of the cellular microenvironment [29]. When examining tissue samples from patients with mammary carcinoma, Mihalcea et al. observed a significant reduction in the heterocellular junctions in affected tissue [30].

Mou et al. observed in an in vitro experiment on reconstituted breast cancer tissue that TCs were in close contact with cancer cells; they hypothesized that TCs are participating in the creation of the nest structures of cancer cells, a typical structure for the spread of cancer [31]. Furthermore, when comparing cultures with cancer cells alone to cultures with cancer cells and stromal cells, including TCs, they observed a higher apoptosis rate in the first group, leading them to believe that TCs also positively affect the survival of cancer cells [31].

The presence of TCs in placental tissue is unique, since placenta is a non-innervated organ. Their presence was confirmed in 2007, specifically in the extraembryonic mesoderm of the villi from human term placenta. Utilizing gap junctions, the TCs formed a network with smooth muscle cells, blood vessels, and myofibroblasts [32]. Given this strategic placement of TCs and the lack of innervation, it is easy to assume that TCs are relevant in cellular signaling and blood flow regulation [33].

The placenta is the place where the physiological exchange between mother and fetus occurs. In a sense, the placenta functions as the lungs, gastrointestinal tract, kidneys, liver, and endocrine organs for the fetus [34]. A guarded balance between proliferation, differentiation, and apoptosis in the placenta is vital for its normal functioning. Pathology of the placenta usually translates into ramifications for the development of the fetus. In pregnancies complicated by preeclampsia, a reduction of utero-placental perfusion is observed, leading to chronic hypoxia of the fetus in late pregnancy. Placental ischemia may trigger the release of placental factors that are responsible for cellular and molecular changes, causing damage or destruction to TCs [33]. The loss of heterocellular contacts provided by TCs can lead to the loss of the hypothetical regulatory function of these cells, negatively affecting the contraction/relaxation of the chorionic villi, which will result in a decrease of the contact surface of the villi with maternal blood and potentially leading to intrauterine growth retardation of the fetus [35].

A more recently published study by Nizyaeva et al. described three types of TCs in placenta, based on their ultrastructural differences. Type I TCs were identified in immature intermediate villi, forming a network in the whole villus, and are characterized by polygonal cell form, irregular nucleus, and with thin surrounding cytoplasm. Type II TCs were found in mature intermediate villi as spindleshaped cells, under the basal membrane of the syncytiotrophoblast, with an oval nucleus and forming a continuous layer beneath the said membrane. Type III TCs are located deeper in the villous stroma, with a stellate cell shape and displaying a larger number of telopodes than type II TCs [36]. The authors also observed that when compared to TCs in the intestinal tract (the place of their first discovery and with the best described cell characteristics), placenta TCs display a low content of cell organelles, in particular mitochondria. And finally, they hypothesized that it is possible for TCs to transform from type I into types II and III and finally, into fibroblast-like and myofibroblast-like cells, during differentiation of villous stroma. This process - fibrosis of the stroma - is physiological in normal placental maturation but is more pronounced in placental pathology, leading to placental insufficiency and intrauterine growth retardation [36].

Table 2 offers a list of possible roles that TCs have in reproductive organs and the placenta. Most of these functions are, of course, based on hypothesis and by extrapolation of functions of TCs located in different organs.