{"paper_id":"3f4867de-4657-4265-b00f-0905090648c5","body_text":"FOLIA MEDICA CRACOVIENSIA\nV ol. L VI, 2, 2016: 17–23\nPL ISSN 0015-5616\nTubal telocytes: factor infertility reason?\nVeronika Aleksandrovych 1, Marek Sajewicz 2, Jerzy A. Walocha 3, \nKrzysztof Gil 1\n1Department of Pathophysiology, Jagiellonian University, Medical College\nul. Czysta 18, 31-121 Kraków, Poland\n2Clinic of Obstetrics and Perinatology, Th e University Hospital\nul. Kopernika 23, 31-501 Kraków, Poland\n3Department of Anatomy, Jagiellonian University, Medical College\nul. Kopernika 12, 31-034 Kraków, Poland\nCorresponding author:  Veronika Aleksandrovych, M.D.; Department of Pathophysiology\nJagiellonian University Medical College\nul. Czysta 18, 31-121 Kraków, Poland\nPhone: +48 12 633 39 47, Fax: +48 12 632 90 56; E-mail: v.aleksandrovych@doctoral.uj.edu.pl\nAbstract: Infertility is actually widespread pathological condition, which aff  ected  one in every four cou-\nples in developing countries. Approximately one third of all cases are connected with tubal factor infertil-\nity, oft en accompanies by endometriosis, acute salpingitis, urogenital infections etc. Th  e newly identifi ed \ntelocytes (TCs) have multiple potential bio-functions and might participate in the fertility problems. \nTh ey infl  uence on structural and functional integrity of oviduct tissue. Despite recent discovery, TCs \ninvolvement in the majority of physiological and pathological processes is still unclear and require sig-\nnifi cant increasing of deep observations and data analysis. Focusing on female reproductive system help \nbetter understands the main reasons of infertility, while evaluation of TCs impact on Fallopian tube and \nuterus contractility might be a key point of its correction. Th  e article summarizes the main features of \ntelocytes in Fallopian tubes, emphasizing their involvement in pathophysiological processes and tubal \nfactor infertility.\nKey words: infertility, telocytes, ICLC instead ICLS, fi broblast-like cells, tubal peristalsis, Fallopian tube. \n\n18 Veronika Aleksandrovych, Marek Sajewicz, et al.\nIntroduction: infertility in statistics\nInfertility remains a highly prevalent condition worldwide. According to the Practice \nCommittee of the American Society for Reproductive Medicine, infertility is a dis-\nease, defi ned by the failure to achieve a successful pregnancy aft  er 12 months or more \nof appropriate, timed unprotected intercourse or therapeutic donor insemination [1]. \nTh ree surveys on the overall prevalence of infertility published in the new millen-\nnium (2004, 2007 and 2012) have very diff  erent results, between 48.5 million and 186 \nmillion. It is estimated that it may aff  ect between 8 and 12% of couples at reproduc-\ntive age, with a probable global incidence average of 9% [2]. Ombelet et al. published \nthat worldwide more than 70 million couples suff er from infertility and bilateral tubal \nocclusion is the most common underlying cause [3]. \nTelocytes: identifi cation and main features\nTelocytes, a novel type of interstitial cell population fi rstly described by Popescu group \nin 2005 and characterized by a small cell body and extremely long prolongations named \ntelopodes (Tps) with alternating thin segments (podomers) and dilated segments (po-\ndoms) [4]. Currently these cells are identifi  ed by transmission electron microscopy \n(TEM), immunohistochemistry and immunofl uorescence. TCs are widely distributed \nin vertebrate (fi sh, reptiles, birds, mammals, including humans) [5]. TCs have been \ndescribed to possess diff erent immunophenotype markers, such as the sialylated trans-\nmembrane glycoprotein CD34 and the tyrosine kinase receptor c-kit/CD117, among \na variety of cavitary and non-cavitary organs: heart (endo-, myo-, epi- and pericardium, \nmyocardial sleeves, heart valves); digestive tract and annex glands (esophagus, stomach, \nduodenum, jejunum, liver, gallbladder, salivary gland, exocrine pancreas); respiratory \nsystem (trachea and lungs); urinary system (kidney, renal pelvis, ureters, bladder, ure-\nthra); female reproductive system (uterus, Fallopian tube, placenta, mammary gland); \nvasculature (blood vessels, thoracic duct); serous membranes (mesentery and pleura); \nother organs (skeletal muscle, meninges an d choroid plexus, neuromuscular spindles, \nfascia lata, skin, eye, prostate, bone marrow) [3–8]. Th  ey also have immunopositivity \nfor numerous markers such as plated-derived growth factor receptor alpha and beta \n(PDGFRα and -β), VEGF , inducible nitric oxide synthase (iNOS), calveolin-1, vimentin, \nconnexin 43, estrogen and progesterone receptors, CD44, desmin, nestin and cadher-\nin-11 [4, 7, 9]. Important to note, that the most applicable method to identify TCs is im-\nmunohistochemistry combined with TEM. Despite the fact that has not yet been found \na specifi c marker for TCs, usually for primary identifi cation scientists use CD34 [9].\nTh e TC interstitial system is composed of cells that by either homocellular or \nheterocellular contacts integrates the overall information from vascular, nervous and \nimmune system, interstitium and stem cells [9]. In pathological condition, these cells \n\n Tubal telocytes: factor infertility reason? 19\ndisplayed ultrastructural change, signifi cantly reduced and progressively disappeared \n[8, 10].\nFallopian tubes as a point of infertility\nFallopian tube is a central organ of human reproduction as plays an essential role in \ntransport of both gametes and embryos and in early embryogenesis [11]. Th e length of \neach oviduct ranges from 15 to 20 cm, while tubal lumen can be from tenths of a mil-\nlimeter to several millimeters depending on the anatomical part. It is lined by simple \ncuboidal or columnar epithelium containing secretory and ciliated cells, which pro-\nduce tubular fl uid and facilitate transport of gametes, respectively [12]. Ciliated cells \nare found predominantly on the apex of the mucosal folds. Th eir reactivity is aff  ected \nby a variety of hormonal and neuronal stimuli. Many pathological conditions associ-\nated with infertility and ectopic pregnancies have been shown either to destroy cilia or \nto reduce ciliary motion or both. [11]. Also, Fallopian tube consists of smooth muscle \ncells (SMC), immunocompetent cells such as leukocytes, and blood vessel cells [13, \n14]. Th e fi rst description of a distinct oviductal cycle in women was made in 1928 [11].\nTubal factor infertility is the most common cause of female infertility and \ndiagnosed in approximately 30% to 35% of younger and older infertile women. Th  e \nmain causes of tubal factor infertility are congenital bilateral agenesis and full oviduct \nblockage, infl ammation of the pelvic organs (in the majority caused by infections), \nendometriosis, former surgical treatment lead to adhesive disease, polyps and \ndiverticula of Fallopian tubes, hydrosalpinx [15]. \nTh e most prevalent cause of tubal factor infertility is pelvic infl  ammatory disease \n(PID) and acute salpingitis. Tubal dama ge from PID causes inflammation and \nlong-term tubal changes, such as fi  mbrial agglutination, fi  mbrial phimosis, tubal \nobstruction, hydrosalpinx, and nodular thickening of the muscularis layer of the \nisthmic portion of the fallopian tube called salpingitis isthmica nodosa. Th  e risk of \nectopic pregnancy can increase sixfold to sevenfold aft er an episode of PID [14]. \nEndometriosis aff ects over 70 million women worldwide and pathophysiological is \nassociated with infl ammation and elevated cytokine levels [12]. Among women with \ntubal factor infertility, endometriosis accounts for 7% to 14% [16]. Th  e expression of \nprogesterone receptors A and B types (PR-A and PR-B) is altered in endometriotic \nlesion stromal cells. Attia et al. showed that PR-A was reduced while PR-B was absent \ncompare with eutopic endometrium [17]. Macrophage migration inhibitory factor \n(MIF) is a potent mitogenic factor for human endothelial cells in vitro  and tumor \nangiogenesis in vivo. Endometriosis leads to increasing of its expression in ectopic and \neutopic endometrium. Moreover, MIF has been shown to stimulate prostaglandin E\n2 \n(PGE2), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), \ninterleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) expression. Y ang \n\n20 Veronika Aleksandrovych, Marek Sajewicz, et al.\net  al. emphases that endometriosis-associated infertility seems to be multifactorial, \ninvolving mechanical, molecular, and genetic mechanisms [18, 19].\nPossible role of telocytes in tubal infertility\nTelocytes are oft en observed between smooth muscle bundles and make contacts with \nsmooth muscle cells. Th ey are located around capillaries and make junctions with fi  -\nbrocytes and pericytes. Urban et al.  observed that TCs were localized mainly in tu-\nnica muscularis externa [20]. Likewise, TCs form heterocellular synapse to mast cells \n(MCs) with their Tps and potentially participated in immunoreactions [21, 22]. Th  e \nlast experiments have shown that TCs also contains in the fi  mbriae of Fallopian tubes \n[6, 23–26]. Although, its spatial distribution gradient decreases from the subepithelial \narea toward serosa measured in the relative numeric density (percentage of TCs out \nof all cells found in that area) (Table 1).\nTable 1. Distribution of telocytes in Fallopian tube stratums.\nArea of the human Fallopian tube Density of TCs (%)\nTh e border epithelium/lamina propria, a ‘belt’ 10 μm thick underneath \nthe basement membrane of the endosalpinx epithelium 18 ± 2\nTh e subepithelial portion of lamina propria (~20 μm thick) 11.7 ± 0.9\nArea, containing the whole lamina propria thickness 9\nTunica muscularis 7.8 ± 1.2\nRemaining zone beneath serosa not assessed\n \nAs TCs make heterocellular contacts with various oviduct interstitium components, \nthey might be involved in intercellular information exchange between various stromal \ncells, or represent a “functional unit” by participating in making a primitive nervous \nsystem through telocytes-exosomes gap junctions-cytoskeleton [18, 22]. \nYang  et al.  reported that in acute salpingitis-affected oviduct tissues, TCs \nwas obviously decreased or lost, severely damaged/degenerated with multiple \nultrastructural abnormalities, such as loss of organelles, numerous swollen nucleus, \nmitochondria and rough endoplasmic reticulum dilatation, cytoplasmic vacuolization, \ndiscontinue or dissolution of Tps, swollen or loss of intercellular junction [21].\nEndometriosis is estrogen-dependent diseas e and might leads to local damage \nof TCs. Massive neutrophils infi  ltration and overproduced inducible nitric oxide \nsynthase (iNOS), COX-2, oxidative stressor (lipid peroxide, LPO) and estradiol in \noviduct tissue suggested mechanism of infl  ammatory-induced TCs damage [21, 22]. \nOn the other hand, he also proposed that TCs damage might contribute to structural \nabnormalities of oviduct [18, 22]. \n\n Tubal telocytes: factor infertility reason? 21\nThe morphology and functional integrity of the Fallopian tube are estrogen \ndependent [13]. Biological activity of 17β-estradiol (E2) is linked to both inhibition and \nstimulation of the interactions between progesterone (P4) and progesterone receptor \n(PR) in the female reproductive tract. Oviduct TCs express estrogen/progesterone \nreceptors, and thus might act as “hormonal sensors” [4, 5, 27–29]. \nKissler et al. observed dysperistalsis of utero-tubal smooth muscle and Y ang  et al., \ntaking into account his results, suggested a possible role of “tubal motility disorder” in \ncontribution to endometriosis-associated tubal factor infertility [18, 29]. Combination \nof estrogen and progesterone is necessary for normal contractility of smooth muscle \ncells in oviduct. Adrenomedullin (ADM) is expressed in epithelial cells of the human \nand rat Fallopian tube. Th  ere is evidence suggesting that circulating ADM levels \nincrease and decrease along with circulating 17β-estradiol levels in humans during the \nmenstrual cycle. Studies have shown that ADM increases ciliary beat frequency and \ndecreases smooth muscle contractility. Estrogens impact on tubal peristalsis. Telocytes \nexpress both types of hormonal receptors (estrogen and progesterone) and might be \ninvolved in tubal contractility and dysperistalsis. Th  ey form heterocellular contacts \nwith smooth muscle cells and have both types of hormonal receptors. Tubal telocytes \ngenerates slow waves within oviduct smooth muscle and has been recognized as \noviduct pacemaker cells [18, 22, 23].\nTCs involved in organization of 3-D extracellular matrix. Th  ey can regulate the \nactivity of neighboring cells (stem ce lls, immunocytes, smooth muscle cells etc.), \nwith intercellular diff  erent signaling mechanisms. TCs damage and 3-D interstitial \narchitectural derangement leads to abnorm al tissue homeostasis and angiogenesis, \ninterstitial fi brosis and consequent reproductive problems [9, 21, 30].\nSecretion of epidermal growth factor and insulin-like growth factors is signifi cantly \nimportant for normal fertilization and embryo development, but it is changed in \nendometriosis affected tissue. Others involved in fibrosis and neo-angiogenesis. \nTCs are positive for growth factors receptors (VEGF , PDGFRα and -β). Numerous \nexperiments have shown involvement of vessels in endometriosis and adenomyosis \npathogenesis. Likewise normal microenvironment and the infl  ammation disease are \nbased on blood circulation in capillaries of the uterus and oviduct. Neo-angiogenesis \nis the main in pathogenesis of tubal ectopic pregnancy. TCs not only located around \ncapillaries and make junctions with fi brocytes and pericytes, they also express growth \nfactors receptors involved in neo-angiogenesis [9, 31–33]. \nTelocytes also surrounded stem cell niches with telopodes and heterocellular \ncontacts. They may participate in oviduc t tissue repair/regeneration processes. \nDamage or loss of TCs will change the acti vity of telocytes-stem cells and decrease \ntissue reparation or renewal capacity, su bsequently inducing development of tissue \nfi brosis. As a result — oviduct dysfunction and infertility. TCs-mediated function-\nspecifi c intercellular signaling contributes to regulate activity of neighboring cells, \n\n22 Veronika Aleksandrovych, Marek Sajewicz, et al.\nincluding involvement in neurotransmission by spreading the slow waves generated \nby the pacemaker interstitial cells of Cajal (ICCs) in the gut, modulating tissue \ndevelopment/remodeling/metabolism, imm unoregulation/immunosurveillance and \nmaintaining homeostasis of the gastrointest inal tube [9, 31, 34, 35]. We postulate that \nsimilar mechanisms concerning telocytes in fallopian tube might be involved in the \npathological processes, leading to infertility of oviductal origin. \nConfl ict of interest\nAuthors declare no confl ict of interest.\nReferences\n 1. Practice Committee of American Society for Reproductive Medicine. Defi  nitions of infertility and \nrecurrent pregnancy loss: a committee opinion. Fertil Steril. 2013; 99 (1): 63.\n 2.  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