**4.1 TCs and signaling processes**

Recently, some of the TCs located on the extracellular matrix of blood vessels were described as having a primary cilium (Cantarero et al., 2011). The presumed functions of such a nonmotile cilium could be:- organizer of the mitotic spindle (Alieva et al., 2004), sensory organelle involved in signal transduction - hedgehog pathway (Singla et al., 2006), mechanical sensing and mechano-chemical conversion in endothelial cells (Egorova et al., 2011; Nauli et al., 2008). By analogy, we can presume that TCs could be involved in the signaling process if located near the stromal colony-forming cells/units in human endometrium or might act as stretch sensors if located near smooth muscle structures in both Fallopian tubes and uterus.

Telocytes in Human Fallopian Tube and Uterus Express Estrogen and Progesterone Receptors 111

endometrial stem cell colony), either by direct stimulation of target cells (immunoreactive cells). Recent evidence suggests that TCs may play a role as putative actors in neo-

In conclusion, the presence of steroid hormone receptors suggests that TCs could behave as sensors controlling the Fallopian tube peristalsis by signaling mechanisms (para- or juxtacrine), depending on ovarian hormone levels, by opposite effects (accelerated by estrogens and delayed by progesterone). Our findings might even explain infertility in patients without any proven Fallopian tube abnormalities. At uterine level, the discovery of TCs is fundamental for a totally new approach regarding the mechanisms controlling myometrial contractility during and outside pregnancy. The evidence for steroid hormone receptors at the level of myometrial TCs might open a path towards the understanding of contractility modulation using steroid hormones. This effect could be the result of intercellular connections between TCs and myocytes. The particular structure of the podoms with energetic (mitochondria) and functional (proteins from ER) resources favours the extension of Tp in the extracellular environment for signalling purposes of for intercellular communication. The steroid receptors occurrence in TCs could also suggest that these cells participate in the exchange of genetic information with other cells (myocytes, immune cells, nerve fibres) or for sensing changes in stromal microenvironment. If some of the supposed functions will be proven, TCs could be used in the future as molecular tools for delivering

This work was partially supported by the "Sectorial Operational Programme" Human Resources Development, financed from the European Social Fund and by the Romanian

Akao, Y.; Iio, A.; Itoh, T.; Noguchi, S.; Itoh, Y.; Ohtsuki, Y. & Naoe, T. (2011).Microvesicle-

Alieva, I.B. & Vorobjev, I.A. (2004).Vertebrate primary cilia: a sensory part of centrosomal

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Carmona, I.C.; Bartolomé, M.J. & Escribano, C.J. (2011).Identification of telocytes in the lamina

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complex in tissue cells, but a "sleeping beauty" in cultured cells? *Cell biology* 

supporting cells for myocardial tissue organization in developing and adult heart.*Journal of cellular and molecular medicine*,Vol.14, No.10, (October 2010) pp. 2531-

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angiogenesis (Manole et al., 2011).

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**7. Acknowledgment** 

**8. References** 

**6. Conclusions** 

TPs usually form and release vesicles (or exosomes) which might indicate the possible involvement of TCs in intercellular communication. For example, in the heart, heterocellular communication between TCs and cardiomyocytes seems to occur by shed vesicles and close apposition (Gherghiceanu et al., 2011). Intercellular signaling can occur by two mechanisms: a paracrine and/or juxtacrine secretion of small signaling molecules and shedding microvesicles which transport 'horizontal' "packets" of macromolecules to the target cells, modifying their physiology. These vesicles can even transport DNA or RNA among neighbouring cells, inducing epigenetic changes (Akao et al., 2010; Zomer et al., 2010). We suspect a complex interplay between TCs, immune cells, cells involved in epithelial or even myometrial regeneration and cancer spreading (Pap et al., 2011).

#### **4.2 TCs and stem cells**

It is known that the remodeling events which take place in the uterus (endo- and myometrium) during implantation and pregnancy are coordinated by sequential actions of estrogen and progesterone (Szotek et al., 2007). TCs, as a special type of stromal cells, could be involved in uterine remodeling since they express ER and PR, and are also located in the lamina propria, beneath the epithelium and in between myocytes. There are fundamental studies that provide evidence that both epithelial and stromal stem/progenitor cells are found in human and mouse uterus (Gargett et al., 2008). The discovery of relationships between TCs and these uterine stem cells could provide new insights into the pathophysiology of various gynecological and obstetrical disorders. In 2009, Shynlova et al. proposed a new model of phenotypic modulation of uterine myocytes during pregnancy. These changes evolve in an early proliferative phase, an intermediate phase of cellular hypertrophy and matrix elaboration, a third phase in which the cells assume a contractile phenotype and the final phase in which cells become highly active and committed to labour. The final phase of myometrial differentiation is postpartum uterine involution. These stages are in fact the result of integration of endocrine signals and mechanical stimulation of the uterus by the growing fetus (Shynlova et al., 2009). In our opinion, TCs could be themselves stem cells (Popescu et al., 2011b), playing a part in muscle regeneration (Popescu et al., 2011a), these processes possibly depending on steroid hormones receptors.

#### **4.3 TCs and immune cells**

TCs often establish contacts with targets, such as smooth muscle cells, nerve fibres, and capillaries (Popescu et al., 2011). Over time, we also described close contact between TCs and cells of the immune system, found in the interstitial space (e.g. eosinophils, plasma cell, etc.). We considered that this is a new type of synapse - the stromal synapse - in addition to the existing neuronal and immunological synapse (Popescu et al., 2005b). The intercellular contact can either be "plain" uniform or "kiss-and-run" multicontact, based on synaptic cleft tracing.

## **5. Perspectives**

TCs can be putative cellular mechanotransducers in smooth muscle tissue. They may sense and translate stretch information for the nucleus, and activate genes responsible for protein synthesis which can influence the surrounding cells by juxta- or paracrine mechanisms. TCs could also be 'hormonal sensors' in human myometrium and the Fallopian tube since they express estrogen and progesterone receptors *in vitro*. The presence of steroid hormone receptors suggests that TCs could also be responsible for myogenic contractility modulation under hormonal control, either by transferring bioactive molecules (towards cells from an endometrial stem cell colony), either by direct stimulation of target cells (immunoreactive cells). Recent evidence suggests that TCs may play a role as putative actors in neoangiogenesis (Manole et al., 2011).
