{"paper_id":"d3d09bd2-2b91-4655-beb8-1f7157512d64","body_text":"FOLIA MEDICA CRACOVIENSIA \nVol. LXII, 3, 2022: 101–109 \nPL ISSN 0015-5616 \nDOI: 10.24425/fmc.2022.142373 \nNotes about telocytes and immunity \nVERONIKA ALEKSANDROVYCH1, ANNA GIL2, ADRIAN PONIATOWSKI1,3 \n1Department of Pathophysiology, Jagiellonian University Medical College, ul. Czysta 18, 31-121 Kraków, Poland \n2Department of Anatomy, Jagiellonian University Medical College, ul. Kopernika 12, 31-034 Kraków, Poland \n3Vassar Brothers Medical Center, Department of Medicine, 45 Reade Place, Poughkeepsie, NY, USA \nCorresponding author: Veronika Aleksandrovych, M.D., Ph.D. \nDepartment of Pathophysiology, Jagiellonian 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@uj.edu.pl \nAbstract: The interstitial cells known as telocytes have been described in various organs. Their role in the \nnormal physiology and pathogenesis of numerous diseases is well known. They have been described in the \ncontext of various diseases (gallstone disease, endometriosis, uterine myoma, hydronephrosis, myocardial \ninfraction, psoriasis, etc.), while their impact on inflammation, involvement in angiogenesis, and repair \nhighlights their part in local homeostasis. What is known about their relationship with the immune \nsystem? Their secretomes, genome, immune profiles, contacts with surrounding cells, and specific loca-\nlization allow us to give a possible explanation for their involvement in pathological pathways. This review \naims to present the roles and features of telocytes in the context of intestinal immunity (the largest in our \nbody), in the spleen, their interactions with immunocytes, and their place in stem cell niches.  \nKeywords: immune response, telocytes, interleukins, cytokines, macrophages. \nSubmitted: 24-Apr-2022; Accepted in the final form: 26-Aug-2022; Published: 15-Sep-2022. \nIntroduction \nThe immune microenvironment is essential for life and all physiological processes in \nboth humans and animal organisms. Aging, tissue regeneration, the tumor microen-\nvironment, allergic and inflammatory reactions, alloimmunization, immune recon-\nstruction and immunosuppression, oncogenesis, immune invasion, autoimmune dis-\neases — these are just some examples of the role that immunocytes play in physiology \nand pathophysiology. The crosstalk between different types of cells is crucial, forming \nthe background of diseases as well as for the maintenance of homeostasis. Each \npopulation of cells should be considered as a piece of a puzzle, and which constitute \nCopyright: © 2022 by the authors. This article is an open access article distributed under the terms and conditions of the Creative \nCommons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, \ndistribution, and reproduction in any medium, provided the original work is properly cited. \n\nan axis of specific physiological action. For instance, platelet-derived mediators (in-\ntegrins, α-granule proteins, δ-granule molecules, and others) may initiate the immune \nresponse. Further, platelet-neutrophil interactions mediate the formation of a specific \naxis to effect NETosis (the formation of neutrophil extracellular traps), while platelet- \ndendritic cells interactions stimulate antigen presentation to T-cells by dendritic cells \n[1]. We also have multiple components of immunity, while different cells are char-\nacterized by diverse properties and their multifaceted nature. Due to their ability to \nform homo- and heterocellular contacts with smooth muscle cells, nerves, immuno-\ncytes (macrophages, mast cells, and lymphocytes), stem cells, melanocytes in the eye, \nerythrocytes, and Schwann cells, as well as their secretion of signaling molecules \n(ectosomes, exosomes, apoptotic bodies), and receptors for growth factors, telocytes \n(TCs) attract great attention and provoke robust discussion as to their nature and role \n[2–5]. They are of mesenchymal origin and make numerous contacts with immuno-\ncytes. Chi et al. conclude that these cells “might be active players in local immunor-\negulation and immunosurveillance, acting as important ‘local data suppliers’ for the \nimmune response” [6]. Morphological characteristics of TCs have been extensively \ndescribed in reviews [2–4]. The development and activity of the immune system are \ncoordinated by cytokines, short-lived small proteins essential for paracrine, autocrine, \nand endocrine signaling. TCs have their own cytokine profiles and may impact macro-\nphage and B cell secretion. M\nultiple hypotheses and speculations, facts and myths, data \nand conclusions all refer to a single pool of cells with described by several synonyms: \n“telocytes”, “interstitial Cajal-like cells”, “fibroblast-like cells”, “PDGFRα+” (platelet- \nderived growth factor receptor alpha), “interstitial pacemaker cells”. In this brief sum-\nmary, we intend to collect the available data about the role of telocytes in the immune \nmicroenvironment by conducting a thorough search on PubMed for all available \nstudies containing the above-mentioned synonymous terms. In particular, we want \nto place emphasis on the network of telocytes and surrounding cells in different parts \nof the immune system, as well as their possible roles. \nTelocytes in the intestinal surface microenvironment \nIntestinal immune regulation has heterogeneous mechanisms, and the working of the \nmucosal immune system is fundamental to the human body. One of the regulatory \nmechanisms involved is the release of acetylcholine from the nonneuronal cholinergic \nsystem, involving the epithelial cells, crypt-villus organoids, immune cells, and in-\ntestinal stem cells [7]. Crypt fission occurs mostly under the action of stem cells [8]. \nSpecial secretory epithelial cells, Paneth cells, are located at the base of epithelial \ninvaginations in the small intestine known as the crypts of Lieberkuhn [9, 10]. They \nmay initiate an immune response and maintain local homeostasis [11]. TCs are pre-\nsent in the intestinal villus-crypt axis [12]. There are different subpopulations of TCs \n102 Veronika Aleksandrovych, Anna Gil, Adrian Poniatowski \n\nin the human gut with possible region-specific roles, differentiated based on their \nimmunohistochemical profile. Their functions include the formation of a 3D network \nin the myenteric plexus, a mechanical role in the submucosal border of the circular \nmuscle layer [13, 14], and they constitute a component of stem cells niches [15]. TCs \nare positive for platelet-derived growth factor α (PDGFRα), which is why in some \nstudies they have been known as “PDGFRα+” cells. Even during the embryonic \nperiod, the circular and longitudinal muscle layers express PDGFRα+, which is essen-\ntial for further differentiation of longitudinal muscles [14]. Both types of muscle in the \nintestine are innervated by enteric motor neurons for the realization of contractile and \nmotor functions. Nitric oxide synthase (NOS) immunopositive neurons are involved \nin muscular contractility and vascular tone [16], while nitric oxide (NO) is a powerful \nagent in the immune system. NO is produced in neurons after stimulation by pro- \ninflammatory cytokines (interferon γ, interleukin 1, and tumor necrosis factor α) due \nto NOS [17, 18]. Of note, TCs may stimulate peritoneal macrophages to produce NOS \nand interleukin-6 through the paracrine pathway [6]. Due to the toxic and protective \neffects of NO, its balance is important for tissue homeostasis (especially for contrac-\ntility, angiogenic, and immunological effects). TCs often have been observed close to \nnerve fibers, including NOS-positive. \nInflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative \ncolitis (UC), are widespread autoimmune disorders characterized by an inflammatory \nprocess with elevated T helper type 1 and type 2 response, while T helpers 17 cells \n(maintained by interleukin 23) are also involved in both diseases [19]. Cytokines and \nchemokines play a role in pathogenesis, depending on the affected region of the \ngastrointestinal tract. T helper (Th) 1-related cytokines (tumor necrosis factor, inter-\nferon-γ, interleukin 12) and Th-17-related (interleukin 17A, 21 and 23) are elevated in \nCrohn’s disease, while ulcerative colitis is associated with overexpression of Th2- \nrelated cytokines (interleukin 4 and 13) [20]. Paneth cells have a central place in \nthe pathogenesis of CD. Their decline leads to CD development and could be con-\nsidered a risk factor. Interestingly, tumor necrosis factor α (TNF α) can also promote \nPaneth cell death [21]. The possible role of TCs in dysmotility and disturbance of \ntissue organization in patients with CD was previously described. In patients with CD, \nTCs have decreased and even disappeared in some observed tissue specimens [22], \nwhile other pathology specimens demonstrate TC damage and reduction in number \n[23]. In addition, they can have morphological modifications and lose CD34 expres-\nsion as a reaction to chronic inflammation. The rapid proliferation of TCs might be \na source of tissue regeneration [24]. Interleukin 33 (a member of the IL-1 family), \nproduced by fibroblast-like cells, is also involved in the pathogenesis of IBD and \nstimulates the production of NO [25]. Intestinal immunity depends not only on gut \nmicrobiota and mucosa immunity. Cells such as telocytes arrive via contacts with \nneighbor cells, signaling and increasing/decreasing in number. \nNotes about telocytes and immunity 103 \n\nTelocytes in the spleen \nOur spleen is the largest secondary lymphoid organ of the immune system and of the \nhuman body. At least two populations of TCs have been identified in the interstitial \nspaces of the spleen. They primarily form homocellular contacts (making a network \nwith other telocytes) or heterocellular contacts (with macrophages, neutrophilic gran-\nulocytes, natural killer cells) [26, 27]. A study on the animal model of Niemann-Pick \ndisease type C, that is on Npc1 mutant mice (Npc1-/-) with enlarged spleens, showed \nan increase in the number of splenic TCs. This might be explained by attempted \nregeneration or the involvement of nursing or recruiting stem cells [28]. In Npc1-/- \nmice, the increase in the number of TCs correlates with an increase in the macrophage \npopulation. Splenic TCs most likely stimulate macrophage growing and secretion of \ncytokines/chemokines. This tendency is common for other organs and tissues. For \ninstance, based on the data, fibrosis is accompanied by reduction in the number of \ntelocytes (however, it is still under discussion whether this is due to a primary or \nsecondary process), while TCs are elevated in the spleen during Niemann-Pick disease \ntype C (often associated with neurodegeneration), and in the oviduct in patients with \nuterine myoma (the data has not yet published). Furthermore, it has been reported \nthat elevated TCs in the human oviduct could correlate with a risk of ectopic preg-\nnancy (tubal) development [29]. An increase in the number of TCs might be con-\nsidered a compensatory trigger for regeneration, assuming the fact of their close \ncontacts with stem cells (niche stem cells). Special close contacts between telocytes \nand mast cells in trachea and in the trigeminal ganglion are known as stromal sy-\nnapses. [3, 30, 31]. \nPreviously, fibroblast-like cells have been described in the spleen: they form close \ncontacts with B cell blasts and enhance interleukin 6 (IL-6) secretion [32]. Peritoneal \nmacrophages, treated with a medium containing cultured telocytes in vitro, secreted \nmore cytokines/chemokines, especially IL-6 [6]. Interleukin 6 belongs to the IL-6 \nfamily cytokines with IL-11 and IL-27, cardiotrophin and cardiotrophin-like cytokine, \noncostatin M, leukemia inhibitory factor, and ciliary neurotrophic factor [33]. IL-6 is \nsecreted by B cells and macrophages, and in both situations TCs indirectly regulate \nIL-6 secretion via interplay with these cells. Of note, IL-6 plays a role in early embryo \nimplantation, the renewal of endometrial blood vessels, stimulation of the production \nof human chorionic gonadotropin by syncytiotrophoblast cells, and proliferative dis-\norders of the endometrium (including endometriosis) [33–35]. The importance of \nIL-6 in female reproductive health cannot be overstated. We also know the impact \nof pregnancy on the TC population: pregnant and non-pregnant uteri have different \namounts of TCs in the myometrium. Telocytes constitute about 7% of the total cell \nnumber in non-pregnant myometrial cell culture and about 3% of the entire cell \npopulation in the myometrium of adult non-pregnant humans [4, 36]. Chi et al. \n104 Veronika Aleksandrovych, Anna Gil, Adrian Poniatowski \n\nconcluded that elevated IL-6 levels might cause an improper endometrial state and \nimplantation failure [6]. We are not sure that can fully explain the intracellular com-\nmunications induced by pregnancy, but the involvement of TCs via stimulation of \nIL-6 production in the physiology of female reproductive health is beyond question. \nOf note, neutralization of IL-6 activity in patients with rheumatoid arthritis (a chronic \ninflammatory process) does not have less efficiency than neutralization of TNFα [33]. \nTelocytes have an impact on both cytokine secretion and have been well described as \na component of connective tissue and the interstitial space. \nSecretome features of telocytes \nThe secretory profile of TCs includes macrophage inflammatory protein 1α (MIP-1α), \nmacrophage inflammatory protein 2 (MIP-2), and monocyte chemoattractant pro-\ntein-1 (MCP-1), also known as chemokine (CC-motif) ligand 2 (CCL2). MCP-1 \nparticipates in the pathogenesis of such diseases as rheumatoid arthritis, cardiovas-\ncular diseases, neuroinflammatory diseases, and different types of oncological dis-\neases. Lately it has been reported that MCP-1 might be considered a biomarker in \npatients with COVID-19 [37–39]. MIP-2 is involved in chemotaxis and cell migration. \nMCP-1 might be a molecular target in the therapy of patients with many diseases, \nespecially given its importance in the tumor microenvironment. The role of telocytes \nin the tumor microenvironment has been described previously [40]. TCs secrete \ninterleukin 2, 6, 10, and 13. Some cell culture experiments demonstrated that some-\ntimes TCs secrete more interleukins than fibroblasts [37]. \nVascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) \nare secreted by TCs, and this process can be discussed beyond just the context of \nangiogenesis and tumorigenesis. VEGF signaling insufficiency speeds up aging and \nleads to “inflammaging” (age-related multiorgan chronic inflammation) [41]. EGF \nimpacts intestinal stem cell proliferation and intestinal homeostasis by promoting \norganoid formation for further regeneration [42]. This growth factor is produced at \nthe base of intestinal crypts in Paneth cells, where TCs are also found. Moreover, two \nadditional substances are secreted by Paneth cells: neuregulin 1 (NRG1) and Wingless \nFamily member 3 (WNT3) during intestinal homeostasis. Neuregulin 1 is detected in \ntelocytes and could compensate for NOS deficiency in endothelial cells (in the kidney \nand heart) [43]. The WNT 3 pathway is important for human malignancies, and its \nupregulation is common for patients with uterine myoma [44], which is characterized \nby a decline in the number of telocytes [18]. \nNotes about telocytes and immunity 105 \n\nStem cell niche and telocytes \nStem cells (immune and tissue) have an epigenetic memory of inflammation that \nincreases sensitivity to next interactions. Inflammatory memory is typical for long- \nlived stem cells with the ability to repair tissue in health and disease [44–46]. It is still \nunknown how they cope with and process recurrent inflammatory-provoking signals, \nbut this mechanism might be more important in the context of autoimmune states. \nTissue homeostasis is maintained through balanced self-renovation, while additional \nstem cells can be activated in particular situations, requiring regeneration or repairing. \nUsually, this process is controlled within “niches” (restricted tissue microenviron-\nments) [47]. TCs have been found in the stem cell niche microenvironments of the \nheart, lung, skeletal muscle, skin, liver, aorta, eye, meninges, and choroid plexus [40, \n48–50]. In addition, they also express stem cell markers on the surface (c-kit, Sca-1, \nOct-4), that mediate their regenerative role and involvement in antitumor immunity. \nOct-4 (octamer-binding transcription factor 4) is essential for oocyte development \nand is important in carcinogenesis, because of its effect on the tumor cell’s differen-\ntiation. In the majority of cases, cells with Oct-4 expression could be considered \ncancer stem cells [51]. Additionally, telocytes have been found in bone marrow [52, \n53]. Hematopoietic stem cells in bone marrow respond to epigenetic and metabolic \nalteration and participate in innate immune memory [54]. We hypothesize that tel-\nocytes might also be involved in this process, because of their action in the prenatal \nand postnatal periods of life. As an essential component of cell stem niche micro-\nenvironment, TCs may regulate the activity of tissue-resident stem cells [48] and be \ninvolved in tissue repair and regeneration. \nFinal remarks \nTo the authors’ knowledge, telocytes are dissimilar to any known cell type due to their \nplasticity and versatility. They have direct and indirect impacts on structure, secretion, \nand expression that in turn affect tissue differentiation, regeneration, repair and im-\nmunity. Instead of a typical conclusion, we want to bring your attention to five \nremarkable facts about telocytes that merit additional study:  \n1. Telocytes have the longest cellular prolongations in the human body.  \n2. Telocytes are more sensitive to hypoxia than fibroblasts.  \n3. Telocytes have been detected in all human organ systems.  \n4. Telocytes react to damage via reduction in number, morphological changes, or \nthe loss the expression of certain markers.  \n5. 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