Interstitial cells of Cajal and telocytes in the gut: twins, related or simply neighbor cells?

Abstract

Abstract:In the interstitium of the connective tissue several types of cells occur. The fibroblasts, responsible for matrix formation, the mast cells, involved in local response to inflammatory stimuli, resident macrophages, plasma cells, lymphocytes, granulocytes and monocytes, all engaged in immunity responses. Recently, another type of interstitial cell, found in all organs so far examined, has been added to the previous ones, the telocytes (TC). In the gut, in addition to the cells listed above, there are also the interstitial cells of Cajal (ICC), a peculiar type of cell exclusively detected in the alimentary tract with multiple functions including pace-maker activity. The possibility that TC and ICC could correspond to a unique cell type, where the former would represent an ICC variant outside the gut, was initially considered, however, further studies have clearly shown that ICC and TC are two distinct types of cells. In the gut, while the features and the roles of the ICC are established, part of the scientific community is still disputing these 'new' interstitial cells to which several names such as fibroblast-like cells (FLCs), interstitial Cajal-like cells or, most recently, PDGFRα + cells have been attributed. This review will detail the main features and roles of the TC and ICC with the aim to establish their relationships and hopefully define the identity of the TC in the gut.

Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA‐mutant GISTs

“…Here, besides confirming these characteristics, we show that these stromal cells often display long, slender cytoplasmic processes that sometimes appear to connect with each other (Figure 1D‐G). The consistent detection of these morphological features in cells positive at CD34 and at PDGFRA IHC (we did not perform a double immunostaining for CD34 and PDGFRA; this constitutes a limitation of our study) is coherent with the existence of a CD34/PDGFRA double‐positive cell type clearly distinct from other cells of the interstitium that can express PDGFRA, that is mast cells, or CD34, that is endothelial cells 27. In particular, endothelial lining often encircles vascular lumens, a feature allowing its clear identification without need of CD31 immunostaining, a useful additional tool for identifying endothelial cells in questionable cases 28.…”

“…Consequently, by analogy with what has been inferred from ICCH in germline KIT ‐mutant settings regarding the relationship between ICC and KIT ‐mutant GIST, TC can be considered the physiological counterpart of IFP. Consistently, it is noticeable that a subtype of TC, differing from the other GI TCs because of its lack of CD34 expression, has been described in the axes of intestinal villi both in humans and mice27 and that intestinal IFPs, unlike gastric ones, are often CD34‐ 1, 2…”

Calcium Signaling in Interstitial Cells: Focus on Telocytes

“…These cells are located in the connective tissue and under the umbrella of this terminology we find reunited cells such as the interstitial cells of Cajal (ICCs), the testosterone-secreting cells of the testis (Leydig cells), the cells in the medulla and cortex of the kidney, the cells found in the connective tissue of the ovary, the aortic valve interstitial cells, etc. [1,2,3,4]. As one can perceive, all these cells differ as to origin and phenotype.…”

“…In fact, while some of these cells might share morphological, immunophenotypical and functional similarities with ICCs, others share the same characteristics with TCs [38]. In a set of reports, Vannucchi and collaborators [1,38,39] solved the controversy regarding the existence of a different population of interstitial Cajal-like cells in the gut. These cells, expressing cluster of differentiation 34 (CD34) and PDGFRα in the gut, were shown to be involved in regulating motility by interaction with ICCs [39].…”

“…Additionally, TCs positive for the alpha smooth muscle antibody (αSMA) or for calreticulin antibody (calret) have also beenconsidered in this classification. Thus, in his articles Vannucchi and collaborators [1,38,39] describe in the bladder, three subtypes of TCs: the first subtype located beneath urothelium was PDGFRα/calret-positive and αSMA/CD34/c-Kit-negative; the second subtype in the deep suburothelium is PDGFRα/calret/αSMA-positive and CD34/c-Kit-negative; and a third TC subtype, PDGFRα/αSMA/c-Kit-negative and CD34/calret-positive, is in the submucosa and detrusor. Díaz-Flores et al emitted the hypothesis that TCs have progenitor capacity and are a source of αSMA+ cells during repair [37].…”