The Telocytes: Ten Years after Their Introduction in the Scientific Literature. An Update on Their Morphology, Distribution, and Potential Roles in the Gut.

Ten years ago, the term 'telocyte' was introduced in the scientific literature to describe a 'new' cell type described in the connective tissue of several organs by Popescu and Faussone-Pellegrini (2010). Since then, 368 papers containing the term 'telocyte' have been published, 261 of them in the last five years. These numbers underscore the growing interest in this cell type in the scientific community and the general acceptance of the name telocyte to indicate this interstitial cell. Most of these studies, while confirming the importance of transmission electron microscopy to identify the telocytes with certainty, highlight the variability of their immune phenotypes. This variability was interpreted as due to (i) the ability of the telocytes to adapt to the different sites in which they reside; (ii) the distinct functions they are likely to perform; and (iii) the existence of telocyte subtypes. In the present paper, an overview of the last 10 years of literature on telocytes located in the gut will be attempted, confining the revision to the morphological findings. A distinct chapter will be dedicated to the recently hypothesized role of the telocytes the intestinal mucosa. Through this review, it will be shown that telocytes, despite their variability, are a unique interstitial cell.

Recently Discovered Interstitial Cell Population of Telocytes: Distinguishing Facts from Fiction Regarding Their Role in the Pathogenesis of Diverse Diseases Called "Telocytopathies".

In recent years, the interstitial cells telocytes, formerly known as interstitial Cajal-like cells, have been described in almost all organs of the human body. Although telocytes were previously thought to be localized predominantly in the organs of the digestive system, as of 2018 they have also been described in the lymphoid tissue, skin, respiratory system, urinary system, meninges and the organs of the male and female genital tracts. Since the time of eminent German pathologist Rudolf Virchow, we have known that many pathological processes originate directly from cellular changes. Even though telocytes are not widely accepted by all scientists as an individual and morphologically and functionally distinct cell population, several articles regarding telocytes have already been published in such prestigious journals as Nature and Annals of the New York Academy of Sciences. The telocyte diversity extends beyond their morphology and functions, as they have a potential role in the etiopathogenesis of different diseases. The most commonly described telocyte-associated diseases (which may be best termed "telocytopathies" in the future) are summarized in this critical review. It is difficult to imagine that a single cell population could be involved in the pathogenesis of such a wide spectrum of pathological conditions as extragastrointestinal stromal tumors ("telocytomas"), liver fibrosis, preeclampsia during pregnancy, tubal infertility, heart failure and psoriasis. In any case, future functional studies of telocytes in vivo will help to understand the mechanism by which telocytes contribute to tissue homeostasis in health and disease.

Therapeutic roles of telocytes in OVA-induced acute asthma in mice.

Telocytes (TCs) newly discovered as the mesenchyme-derived interstitial cells were found to have supportive effects on mesenchymal stem cells (MSCs). The present study aimed at investigating effects of TCs or TCs gathered with MSCs on experimental airway inflammation and hyper-responsiveness. The TCs were isolated from the lung tissue of the female BALB/c mice. The ovalbumin (OVA)-induced asthma model was established. TCs (1 × 106 /2 × 106 ) and/or MSCs (1 × 106 ) were injected through mice tail vein for consecutive three days before OVA excited the mice. This study at first demonstrated that the transplantation of TCs could improve allergen-induced asthma by obviously inhibiting airway inflammation and airway hyper-responsiveness preclinically, with the down-regulation of Th2-related cytokine IL-4, transcription factor GATA-3 and Th2 cell differentiation, while up-regulation of Th1-related cytokine IFN-γ, transcription factor T-bet and Th1 cells proliferation in asthma, just like MSCs. Co-transplantation of TCs with MSCs showed better therapeutic effects on experimental asthma, even though the therapeutic effects of TCs alone were similar to those of MSCs alone. TCs and the combination of TCs with MSCs could improve the airway inflammation and airway hyper-responsiveness and can be a new alternative for asthma therapy.

Telocytes of the human adult trigeminal ganglion.

Telocytes (TCs) are typically defined as cells with telopodes by their ultrastructural features. Their presence was reported in various organs, however little is known about their presence in human trigeminal ganglion. To address this issue, samples of trigeminal ganglia were tested by immunocytochemistry for CD34 and examined by transmission electron microscopy (TEM). We found that TCs are CD34 positive and form networks within the ganglion in close vicinity to microvessels and nerve fibers around the neuronal-glial units (NGUs). TEM examination confirmed the existence of spindle-shaped and bipolar TCs with one or two telopodes measuring between 15 to 53 µm. We propose that TCs are cells with stemness capacity which might contribute in regeneration and repair processes by: modulation of the stem cell activity or by acting as progenitors of other cells present in the normal tissue. In addition, further studies are needed to establish if they might influence the neuronal circuits.

The History of Telocyte Discovery and Understanding.

Telocytes (TCs) are identified as a peculiar cell type of interstitial cells in various organs. The typical features of TCs from the other cells are the extending cellular process as telopodes with alternation of podomeres and podoms. Before the year of 2010, TCs were considered as interstitial Cajal-like cells because of the similar morphology and immunohistochemical features with interstitial cells of Cajal which were found more than 100 years ago and considered to be pacemakers for gut motility. Subsequently, it demonstrated that TCs were not Cajal-like cells, and thus the new name "telocyte" was proposed in 2010. With the help of different techniques, e.g., transmission electron microscopy, immunohistochemistry, or omics science, TCs have been detected in various tissues and organs from different species. The pathological role of TCs in different diseases was also studied. According to observation in situ or in vitro, TCs played a vital role in mechanical support, signaling transduction, tissue renewal or repair, immune surveillance, and mechanical sensor via establishing homo- or heterogenous junctions with neighboring cells to form 3D network or release extracellular vesicles to form juxtacrine and paracrine. This review will introduce the origin, distribution, morphology, functions, omics science, methods, and interaction of TCs with other cells and provide a better understanding of the new cell type.

Morpho-functional changes of cardiac telocytes in isolated atrial amyloidosis in patients with atrial fibrillation.

Telocytes are interstitial cells with long, thin processes by which they contact each other and form a network in the interstitium. Myocardial remodeling of adult patients with different forms of atrial fibrillation (AF) occurs with an increase in fibrosis, age-related isolated atrial amyloidosis (IAA), cardiomyocyte hypertrophy and myolysis. This study aimed to determine the ultrastructural and immunohistochemical features of cardiac telocytes in patients with AF and AF + IAA. IAA associated with accumulation of atrial natriuretic factor was detected in 4.3-25% biopsies of left (LAA) and 21.7-41.7% of right (RAA) atrial appendage myocardium. Telocytes were identified at ultrastructural level more often in AF + IAA, than in AF group and correlated with AF duration and mitral valve regurgitation. Telocytes had ultrastructural signs of synthetic, proliferative, and phagocytic activity. Telocytes corresponded to CD117+, vimentin+, CD34+, CD44+, CD68+, CD16+, S100-, CD105- immunophenotype. No significant differences in telocytes morphology and immunophenotype were found in patients with various forms of AF. CD68-positive cells were detected more often in AF + IAA than AF group. We assume that in aged AF + IAA patients remodeling of atrial myocardium provoked transformation of telocytes into "transitional forms" combining the morphological and immunohistochemical features with signs of fibroblast-, histiocyte- and endotheliocyte-like cells.

Melatonin administration provokes the activity of dendritic reticular cells in the seminal vesicle of Soay ram during the non-breeding season.

Dendritic cells (DCs) are innate immune cells which engulf, process and present antigens to the naïve T-lymphocyte cells. However, little is known about the effect of melatonin on the DCs. The present study aimed to investigate the morphology and distribution of the DCs by transmission electron microscopy and Immunohistochemistry after melatonin administration. A total of 8 out of 15 adult ram was randomly selected to receive the melatonin implant and the remaining 7 animals received melatonin free implants. DCs showed positive immunoreactivity for CD117, S-100 protein and CD34. There is an obvious increase in the number of the positive immunoreactive cells to CD3, estrogen receptor alpha and progesterone in the treated groups. The expression of CD56 and MHCII in the DCs was abundant in the treated groups. The ultrastructure study revealed that melatonin exerts a stimulatory effect on the DCs which was associated with increment in the secretory activity of DCs. The secretory activity demarcated by an obvious increase in the number of mitochondria, cisternae of rER and a well-developed Golgi apparatus. The endosomal- lysosomal system was more developed in the treated groups. A rod-shaped Birbeck granule was demonstrated in the cytoplasm of the melatonin treated group. DCs were observed in a close contact to telocytes, T-Lymphocytes, nerve fibers and blood vessels. Taken together, melatonin administration elicits a stimulatory action on the DCs and macrophages through increasing the size, the number and the endosomal compartments which may correlate to increased immunity.

The oral mucosa: Epithelial professional phagocytes, lymphatics, telocytes, and false telocytes.

BACKGROUND: The oral mucosa protects the underlying tissue from mechanical damage as well as from the entry of exogenous particles and microorganisms. Telocytes (TCs) are disputed stromal cells featuring peculiarly long and thin processes with uneven calibre known as telopodes, which play a number of roles within the interstitia. The present study aimed to test the key markers recommended for discriminating between TCs and false TCs in samples of normal oral mucosa. METHODS: Archived paraffin-embedded oral mucosa samples were tested by means of immunohistochemistry with the following markers: CD34, D2-40, CD31 and CD68. RESULTS: The epithelial expression of CD68, D2-40 and CD34 was detected. Two subsets of CD34-expressing stromal cells were identified, large cells with telopodial processes, presumably of the hematopoietic lineage, and spindle-shaped TC-like cells. Macrophages and TC-like cells within the lamina propria expressed CD68. The lymphatic endothelia were found to express CD31 and D2-40, but not CD34. Sprouting lymphangiogenesis was demonstrated by the lymphatic endothelial tip cells, which were projecting thin processes within the connective stroma. CONCLUSIONS: The epithelial expression of CD68 suggests the professional phagocytic potential of the oral epithelium. Regarding the TCs and TC-like cells in the oral mucosa they could not be accurately distinguished from other possible cell types, neither on morphological basis (evidence of telopodes) nor by use of panels of markers which include CD34.