Telocytes in the female reproductive system: An overview of up-to-date knowledge

Telocytes are emerging cell population localized in the stroma of numerous organs, characterized by a distinctive morphology – small cell body with very long, slender prolongations, termed telopodes. Those cells can be found in the whole female reproductive system: in the vagina, uterus, oviducts and ovaries, mammary glands and also in the placenta. In our review, we aim at complete and transparent revision of the current knowledge of telocytes’ localization and function, enriched by the analysis of the possible future direction of development of their clinical applications. The function of telocytes in the reproductive system has not been fully elucidated yet; however, many researchers point at their role in the regulation of local microenvironment, myogenic contractile mechanism, bioelectrical signaling, immunomodulation and regulation of blood flow. Additionally, previous research suggests that telocytes might act as sex hormone level sensors and are connected with pregnancy maintenance. As the morphology and number of those cells change under pathological conditions, such as pre-eclampsia, endometriosis and ovarian failure, there is a chance that they may contribute to therapy of abovementioned conditions. The impact of telocytes on stem cells and angiogenesis has been proven in many organs, and may be useful in regenerative medicine of the female reproductive system. A recently found connection between the proliferation rate of breast cancer cells and stromal cells like telocytes might be a step forward to the management of mammary gland neoplasms. Key words ovary, uterus, placenta, telocytes, telopodes

(59) - Varga I, Urban L, Kajanová M, Polák Š. Functional histology and pos- sible clinical significance of recently discovered telocytes inside the female reproductive system. Arch Gynecol Obstet. 2016;294:417–422. - Popescu LM, Andrei F, Hinescu ME. Snapshots of mammary gland interstitial cells: Methylene-blue vital staining and c-kit immunopos- itivity. J Cell Mol Med. 2005;9:476–477. - Shafik A, El-Sibai O, Shafik I, Shafik AA. Immunohistochemical iden- tification of the pacemaker Cajal cells in the normal human vagina. Arch Gynecol Obstet. 2005;272:13–16. - Ciontea SM, Radu E, Regalia T, et al. C-kit immunopositive intersti- tial cells (Cajal-type) in human myometrium. J Cell Mol Med. 2005;9:407–420. - Urban L, Miko M, Kajanova M, et al. Telocytes (interstitial Cajal-like cells) in human Fallopian tubes. Bratisl Lek Listy. 2016;117:263–267. - Suciu L, Popescu LM, Gherghiceanu M. Human placenta: De visu demonstration of interstitial Cajal-like cells. J Cell Mol Med. 2007;11:590–597. - Faussone-Pellegrini MS, Cortesini C, Romagnoli P. Ultrastructure of the tunica muscularis of the cardial portion of the human esophagus and stomach, with special reference to the so-called Cajal’s intersti- tial cells. Arch Ital Anat Embriol. 1977;82:157–177. - Pieri L, Vannucchi MG, Faussone-Pellegrini MS. Histochemical and ultrastructural characteristics of an interstitial cell type different from ICC and resident in the muscle coat of human gut. J Cell Mol Med. 2008;12:1944–1955. - Duquette RA, Shmygol A, Vaillant C, et al. Vimentin-positive, c-kit- negative interstitial cells in human and rat uterus: A role in pacemak- ing? Biol Reprod. 2005;72:276–283. - Shafik A, Shafik AA, El Sibai O, Shafik IA. Specialized pacemaking cells in the human Fallopian tube. Mol Hum Reprod. 2005;11:503–505. - Popescu LM, Faussone-Pellegrini MS. TELOCY TES – A case of ser- endipity: The winding way from Interstitial Cells of Cajal (ICC), via Interstitial Cajal-Like Cells (ICLC) to TELOCY TES. J Cell Mol Med.2010;14:729–740. - Edelstein L, Fuxe K, Levin M, Popescu BO, Smythies J. Telocytes in their context with other intercellular communication agents. Semin Cell Dev Biol. 2016;55:9–13. - Mihalcea CE, Moroşanu AM, Murăraşu D, et al. Particular molecular and ultrastructural aspects in invasive mammary carcinoma. Rom J Morphol Embryol. 2015;56:1371–1381. - Bei Y, Zhou Q, Sun Q, Xiao J. Telocytes in cardiac regeneration and repair. Semin Cell Dev Biol. 2016;55:14–21. - Kostin S. Myocardial telocytes: A specific new cellular entity. J Cell Mol Med. 2010;14:1917–1921. - Mirancea N. Telocyte – A particular cell phenotype. Infrastructure, relationships and putative functions. Rom J Morphol Embryol. 2016;57:7–21. - Chang Y, Li C, Lu Z, Li H, Guo Z. Multiple immunophenotypes of car- diac telocytes. Exp Cell Res. 2015;338:239–244. - Kostin S. Cardiac telocytes in normal and diseased hearts. Semin CellDev Biol. 2016:55:22–30. - Cretoiu SM, Popescu LM. Telocytes revisited. Biomol Concepts. 2014;5:353–369. - Faussone-Pellegrini MS, Gherghiceanu M. Telocyte’s contacts. SeminCell Dev Biol. 2016;55:3–8. - Suciu L, Popescu LM, Gherghiceanu M, et al. Telocytes in human term placenta: Morphology and phenotype. Cells Tissues Organs.2010;192:325–339. - Ibba-Manneschi L, Rosa I, Manetti M. Telocyte implications in human pathology: An overview. Semin Cell Dev Biol. 2016;55:62–69. - Fertig ET, Gherghiceanu M, Popescu LM. Extracellular vesicles release by cardiac telocytes: Electron microscopy and electron tomography. J Cell Mol Med. 2014;18:1938–1943. - Gherghiceanu M, Popescu LM. Cardiac telocytes – their junctions and functional implications. Cell Tissue Res. 2012;348:265–279. - Cretoiu D, Cretoiu SM. Telocytes in the reproductive organs: Current understanding and future challenges. Semin Cell Dev Biol. 2016;55:40–49. - Popescu LM, Fertig ET, Gherghiceanu M. Reaching out: Junctions between cardiac telocytes and cardiac stem cells in culture. J Cell Mol Med. 2016;20:370–380. - Cismasiu VB, Popescu LM. Telocytes transfer extracellular vesicles loaded with microRNAs to stem cells. J Cell Mol Med. 2015;19:351–358. - Cretoiu SM, Radu BM, Banciu A, et al. Isolated human uterine telo- cytes: Immunocytochemistry and electrophysiology of T-type cal- cium channels. Histochem Cell Biol. 2015;143:83–94. - Rosenbaum ST, Svalø J, Nielsen K, Larsen T, Jørgensen JC, Bouche- louche P. Immunolocalization and expression of small-conductance calcium-activated potassium channels in human myometrium. J Cell Mol Med. 2012;16:3001–3008. - Sheng J, Shim W, Lu J, et al. Electrophysiology of human cardiac atri- al and ventricular telocytes. J Cell Mol Med. 2014;18:355–362. - Cretoiu SM, Cretoiu D, Marin A, Radu BM, Popescu LM. Telocytes: Ultrastructural, immunohistochemical and electrophysiological char- acteristics in human myometrium. Reproduction. 2013;145:357–370. - Edelstein L, Smythies J. The role of telocytes in morphogenetic bio- electrical signaling: Once more unto the breach. Front Mol Neurosci.2014, 7, 41. - Yang C, Xiao J. Editorial. Telocytes in regeneration and repair. Curr Stem Cell Res Ther. 2016;11:382. - Díaz-Flores L, Gutiérrez R, Goméz MG, Sáez FJ, Madrid JF. Behaviour of telocytes during physiopathological activation. Semin Cell Dev Biol. 2016;55:50–61. - Xiao J, Chen P, Qu Y, et al. Telocytes in exercise-induced cardiac growth. J Cell Mol Med. 2016;20:973–979. - Popescu LM. The tandem: Telocytes – stem cells. Int J Biol Biomed Eng. 2011;5:83–92. - Enciu AM, Popescu LM. Telopodes of telocytes are influenced in vitro by redox conditions and ageing. Mol Cell Biochem. 2015;410:165–174. - Hatta K, Huang ML, Weisel RD, Li RK. Culture of rat endometrial telo- cytes. J Cell Mol Med. 2012;16:1392–1396. - Creţoiu SM, Creţoiu D, Popescu LM. Human myometrium – the ultra- structural 3D network of telocytes. J Cell Mol Med. 2012;16:2844–2849. - Aleksandrovych V, Walocha JA, Gil K. Telocytes in female reproduc- tive system (human and animal). J Cell Mol Med. 2016;20:994–1000. - Roatesi I, Radu BM, Cretoiu D, Cretoiu SM. Uterine telocytes: A review of current knowledge. Biol Reprod. 2015;93:10. - Yang XJ, Yang J, Liu Z, Yang G, Shen ZJ. Telocytes damage in endo- metriosis-affected rat oviduct and potential impact on fertility. J Cell Mol Med. 2015;19:452–462. - He X, Chen Q. Reduced expressions of connexin 43 and VEGF in the first-trimester tissues from women with recurrent pregnancy loss. Reprod Biol Endocrinol. 2016;14:46. - Cretoiu D, Ciontea SM, Popescu LM, Ceafalan L, Ardeleanu C. Intersti- tial Cajal-like cells (ICLC) as steroid hormone sensors in human myo- metrium: Immunocytochemical approach. J Cell Mol Med. 2006;10:789–795. - Cretoiu SM, Cretoiu D, Suciu L, Popescu LM. Interstitial Cajal-like cells of human Fallopian tube express estrogen and progesterone recep- tors. J Mol Histol. 2009;40:387–394. - Gevaert T, De Vos R, Van Der Aa F, et al. Identification of telocytes in the upper lamina propria of the human urinary tract. J Cell Mol Med. 2012;16:2085–2093. - Albulescu R, Tanase C, Codrici E, Popescu DI, Cretoiu SM, Popescu LM. The secretome of myocardial telocytes modulates the activity of car- diac stem cells. J Cell Mol Med. 2015;19:1783–1794. - Ullah S, Yang P, Zhang L, et al. Identification and characterization of telo- cytes in the uterus of the oviduct in the Chinese soft-shelled turtle, Pel- odiscus sinensis: TEM evidence. J Cell Mol Med. 2014;18: 2385–2392. - Díaz-Flores L, Gutiérrez R, García MP, et al. Uptake and intracytoplas- mic storage of pigmented particles by human CD34+ stromal cells/ telocytes: Endocytic property of telocytes. J Cell Mol Med. 2014;18:2478–2487. - Chi C, Jiang XJ, Su L, Shen ZJ, Yang XJ. In vitro morphology, viability and cytokine secretion of uterine telocyte-activated mouse perito- neal macrophages. J Cell Mol Med. 2015;19:2741–2750. - Campeanu RA, Radu BM, Cretoiu SM, et al. Near-infrared low-level laser stimulation of telocytes from human myometrium. Lasers Med Sci. 2014;29:1867–1874. - Yang P, Zhu X, Wang L, et al. Telocytes as a novel interstitial cells pres- ent in the magnum of chicken oviduct. Cell Transplant. 2016 [ahead of print]. - Yang J, Chi C, Liu Z, Yang G, Shen ZJ, Yang XJ. Ultrastructure dam- age of oviduct telocytes in rat model of acute salpingitis. J Cell Mol Med. 2015;19:1720–1728. - Yang XJ, Xu JY, Shen ZJ, Zhao J. Immunohistochemical alterations of Cajal-like type of tubal interstitial cells in women with endometrio- sis and tubal ectopic pregnancy. Arch Gynecol Obstet. 2013;288:1295–1300. - Liu T, Wang S, Li Q, Huang Y, Chen C, Zheng J. Telocytes as potential targets in a cyclophosphamide-induced animal model of premature ovarian failure. Mol Med Rep. 2016;14:2415–2422. - Gherghiceanu M, Popescu LM. Interstitial Cajal-like cells (ICLC) in human resting mammary gland stroma. Transmission electron micro- scope (TEM) identification. J Cell Mol Med. 2005;9:893–910. - Mou Y, Wang Y, Li J, et al. Immunohistochemical characterization and functional identification of mammary gland telocytes in the self-assembly of reconstituted breast cancer tissue in vitro. J Cell Mol Med. 2013;17:65–75. - Petre N, Rusu MC, Pop F, Jianu AM. Telocytes of the mammary gland stroma. Folia Morphol (Warsz). 2015 [ahead of print]. - Bosco CB, Díaz EG, Gutierrez RR, 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;11:420–425.