**3. Human urinary bladder**

The urinary bladder is a complex organ which modifies its volume and shapes several times during the day following filling and micturition. Filling happens gradually during the time while micturition happens in a unique and sustained emission of the urine. The cells of the lining epithelium (urothelium) dramatically changes their shape and height; under the urothelium, there are two regions: the upper lamina propria (ULP) and the deep lamina propria (DLP), with different morphological organization and function; the detrusor is the muscle coat responsible for organ relaxation and contraction. Region-specific mechanical and functional interrelationships between all the urinary bladder components are at the basis of correct and coordinated behavior.

## **3.1 Bladder telocyte network in healthy condition**

In the bladder, unlike in other organs, a more complex picture comes out [33, 35]. As is the case in the gut, the bladder TCs form complex networks and make contacts either between themselves or with other cell types; however, depending on their location, they show different immunohistochemical properties and ultrastructural peculiarities. The main differences are detected between the TCs located in the sub-urothelial connective tissue (upper lamina propria, ULP) and those located in the submucosa (also referred to as deep lamina propria) and detrusor. The TCs in the ULP is PDGFRα+ and CD34- while those in the submucosa and detrusor are CD34+ and PDGFRα- (**Figure 5A** and **B**). Moreover, while the TCs immediately below the urothelium express only the PDGFRα and form a homo-cellular network, the other sub-urothelial TCs are also α-SMA+ (**Figure 5A**)

**77**

**Figure 5.**

*Scale bar: A, B = 100 μm.*

the micturition.

*Telocytes: New Connecting Devices in the Stromal Space of Organs*

and under the transmission electron microscope show a larger body and cell processes possessing attachment plaques with the connective tissue like the fibronexuses typical of myofibroblasts. Further, these TCs establish extended regions of simple apposition with the myofibroblasts, thus forming a 3D mixed network (**Figure 5A**). This mixed network together with the homo-cellular networks that the TCs make in the remaining portions of the bladder constitutes the scaffolding to guarantee the organ integrity during distention and relaxation [33, 35, 37, 56]. However, other specific roles have been assumed for the bladder TCs, particularly for those located in the ULP. The TCs lining the urothelium is quite peculiar, because of their location and immunolabeling [33, 38]. As already discussed, the PDGFRα+ TCs located immediately beneath the intestinal crypts appear to be cells engaged in controlling the proliferation and differentiation of the stem cells resident in the crypts [23]. Likewise, sub-urothelial TCs could play similar functions. Immediately below those TCs, there is the TCs/myofibroblast network and both cell types form gap junctions and express the Cx43 protein, are close to nerve varicosities, express the vanilloid, the ATP, the purine and the muscarinic receptors and contain the cGMP, the target molecule of NO [35]. These features support the hypothesis that these cells have a role as intermediaries in propagating chemical or electrical stimuli locally generated, as well as a role as the target of the paracrine activity of the urothelium and the nervous stimuli [35, 38, 57]. The importance of these roles is plenty understood, since the ULP and the urothelium constitute a sensory system capable of perceiving mechanical and chemical stimuli and whose integrated responses control the efferent pathways on the detrusor and

*TCs networks in the human urinary bladder. (A) PDGFRα (green) and α-SMA (red) immunolabeling. A monolayer of PDGFRα+ TC lines the urothelium (U). In the remaining upper portion of the lamina propria (ULP) a mixed network made by PDGFRα+/α-SMA+ TC (hybrid TC) and α-SMA+ myofibroblasts is present. (B) CD34+ TC form a homo-cellular network in the deep lamina propria (DLP) and detrusor (D).* 

*DOI: http://dx.doi.org/10.5772/intechopen.89383*

*Telocytes: New Connecting Devices in the Stromal Space of Organs DOI: http://dx.doi.org/10.5772/intechopen.89383*

### **Figure 5.**

*Innovations in Cell Research and Therapy*

gastroparesis [54].

this tumor [55].

**3. Human urinary bladder**

basis of correct and coordinated behavior.

**3.1 Bladder telocyte network in healthy condition**

UC colonic specimens the loss of TCs was paralleled by an increase in the number of α-SMA+ myofibroblasts [51]. This last observation suggests that during pathologic processes a subset of TC could undergo phenotypic changing, possibly contributing to the increase in the profibrotic myofibroblast population [41]. However, double immunolabeling for CD34 (as TC marker) and α-SMA did not reveal the presence of CD34+/α-SMA+ transitioning stromal cells in the colonic wall of UC patients, which makes unlikely the aforementioned hypothesis [51]. Also, electron microscopy investigations of different pathological tissues (e.g., failing human heart, fibrotic skin) have clearly shown that fibrosis is accompanied by TC degenerative processes rather than by activation/transformation into myofibroblasts [52, 53]. As the findings in the CD and UC intestinal tissues, a loss of TCs have also been reported in the neuromuscular compartment of the fibrotic gastric wall of patients with systemic sclerosis, where it likely contributes to gastric dysmotility clinically manifesting as delayed gastric emptying or

Besides IBD, recent evidence suggests that the TCs might be a cell source of certain kinds of gastrointestinal stromal tumors (GIST) [55]. While ICCs hyperplasia has been identified as a crucial pathogenic feature of KIT-mutant GIST, it has been proposed that the TCs could represent the physiological counterpart of PDGFRa-mutant GIST and inflammatory fibroid polyps [55]. Indeed, a pathogenic relationship between TCs hyperplasia and both inflammatory fibroid polyps and PDGFRa-mutant GIST has been suggested. Moreover, the term "telocytoma" was proposed for defining inflammatory fibroid polyps, since it conveys both the pathogenic (neoplastic) and histotypic ("telocytary") nature of

The urinary bladder is a complex organ which modifies its volume and shapes several times during the day following filling and micturition. Filling happens gradually during the time while micturition happens in a unique and sustained emission of the urine. The cells of the lining epithelium (urothelium) dramatically changes their shape and height; under the urothelium, there are two regions: the upper lamina propria (ULP) and the deep lamina propria (DLP), with different morphological organization and function; the detrusor is the muscle coat responsible for organ relaxation and contraction. Region-specific mechanical and functional interrelationships between all the urinary bladder components are at the

In the bladder, unlike in other organs, a more complex picture comes out [33, 35]. As is the case in the gut, the bladder TCs form complex networks and make contacts either between themselves or with other cell types; however, depending on their location, they show different immunohistochemical properties and ultrastructural peculiarities. The main differences are detected between the TCs located in the sub-urothelial connective tissue (upper lamina propria, ULP) and those located in the submucosa (also referred to as deep lamina propria) and detrusor. The TCs in the ULP is PDGFRα+ and CD34- while those in the submucosa and detrusor are CD34+ and PDGFRα- (**Figure 5A** and **B**). Moreover, while the TCs immediately below the urothelium express only the PDGFRα and form a homo-cellular network, the other sub-urothelial TCs are also α-SMA+ (**Figure 5A**)

**76**

*TCs networks in the human urinary bladder. (A) PDGFRα (green) and α-SMA (red) immunolabeling. A monolayer of PDGFRα+ TC lines the urothelium (U). In the remaining upper portion of the lamina propria (ULP) a mixed network made by PDGFRα+/α-SMA+ TC (hybrid TC) and α-SMA+ myofibroblasts is present. (B) CD34+ TC form a homo-cellular network in the deep lamina propria (DLP) and detrusor (D). Scale bar: A, B = 100 μm.*

and under the transmission electron microscope show a larger body and cell processes possessing attachment plaques with the connective tissue like the fibronexuses typical of myofibroblasts. Further, these TCs establish extended regions of simple apposition with the myofibroblasts, thus forming a 3D mixed network (**Figure 5A**). This mixed network together with the homo-cellular networks that the TCs make in the remaining portions of the bladder constitutes the scaffolding to guarantee the organ integrity during distention and relaxation [33, 35, 37, 56]. However, other specific roles have been assumed for the bladder TCs, particularly for those located in the ULP. The TCs lining the urothelium is quite peculiar, because of their location and immunolabeling [33, 38]. As already discussed, the PDGFRα+ TCs located immediately beneath the intestinal crypts appear to be cells engaged in controlling the proliferation and differentiation of the stem cells resident in the crypts [23]. Likewise, sub-urothelial TCs could play similar functions. Immediately below those TCs, there is the TCs/myofibroblast network and both cell types form gap junctions and express the Cx43 protein, are close to nerve varicosities, express the vanilloid, the ATP, the purine and the muscarinic receptors and contain the cGMP, the target molecule of NO [35]. These features support the hypothesis that these cells have a role as intermediaries in propagating chemical or electrical stimuli locally generated, as well as a role as the target of the paracrine activity of the urothelium and the nervous stimuli [35, 38, 57]. The importance of these roles is plenty understood, since the ULP and the urothelium constitute a sensory system capable of perceiving mechanical and chemical stimuli and whose integrated responses control the efferent pathways on the detrusor and the micturition.
