**6. Conclusion and future overlook for telocytes' study**

In conclusion, this review of the literature data indicates that TCs, depending on their location, may display different immunohistochemical properties, ultrastructural peculiarities and form complex networks making contacts either between themselves or with other cell types. Further, our current knowledge of TCs allows the following conclusions on the role(s) that these cells may play, some of which might be common to the different organs and some be organ-/region-specific.

1.In the stromal space of all the organs taken into account, TCs appear as connecting cells. Reasonably, TCs, due to their homo- and hetero-cellular contacts, can be considered as *connecting devices* playing either common or region-specific roles. These contacts might be merely mechanical or sites of cross-talking between TCs and other cell types establishing intercellular molecular exchanges. Spatial relationships also suggest an involvement of the TCs network in the coordination of tissue homeostasis in response to local functional demands.

The involvement in tissue homeostasis might be explained by the heterogeneity of TCs depending on their location.

2.TCs might be engaged in *controlling the proliferation and differentiation of the stem cells* and, either in the adulthood or during organ differentiation, wherever they are located, these cells might be considered as a pool of mesenchymal stromal cells

As an example, in the gastrointestinal tract and the urinary bladder, the subepithelial plexus formed by TCs likely supports the stem cell proliferation and epithelial renewal and, the TCs located in the muscle coat, might differentiate into ICCs

**85**

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

undoubtedly accompanies myometrial hypertrophy.

and, undergoing to phenotypic changes, become a cell source of gastrointestinal stromal tumors such as GIST. A shift toward a myofibroblast phenotype has been

In the female genital tract, although there are no reported interactions with stem cells, a role for TCs in this direction cannot be overlooked because neo-angiogenesis

Moreover, in the heart, a special inter-relation exists between TCs and cardiac stem cells based on the exchange of information via extracellular vesicles which shuttle miRNA or by direct connections through typical and atypical junctions. The secretome of TCs might enhance the proliferation and differentiation of cardiac stem cells. Suggestions were also made regarding the possibility of their role in the re-activation of dormant myocardial precursors during the repair of the adult heart, while in embryo TCs act as inductors/regulators of differentiation during

3.The TCs scaffold located in all the hollow organs follows organ distension and relaxation likely to avoid anomalous organ deformation and to control blood vessels closure or rheology. This is *a mechanical role* whose importance has been demonstrated in some gastrointestinal pathologies, where TCs loss provokes severe architectural derangement and contributes to the altered 3D ECM organization in the fibrotic intestinal wall. In the uterus, TCs can function as a sensor for the mechanical stress exerted on the uterine wall, allowing uniform uterine growth during pregnancy, by mechanosensitive coordination due to the existence of different ionic channels which can be modulated by pharma-

Moreover, TCs can also be regarded as chemical sensors as it was hypothesized for the human uterus and fallopian tube, where TCs might play an important role in the uterine contraction mechanism due to the presence of estrogen and progester-

4.Because of the anatomical complexity of the hollow organs and the great

In the gastrointestinal tract, a particular role is played by the intramuscular hetero-cellular TCs network in *supporting the spreading of the slow waves generated by the ICCs*, which are electrically coupled to the smooth muscle cells, thus contributing to the regulation of gastrointestinal motility. In agreement with this hypothesis is the evidence that the simultaneous reductions in the TCs and ICCs account for the intestinal dysmotility characterizing the IBD. In the urinary bladder, the sub-urothelial TCs likely play a role as intermediaries in propagating chemical or electrical stimuli locally generated being the target of the paracrine activity of the urothelium and the nervous system. 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, responses that are lost in urinary

In female genital tract, TCs seems to lack in regular slow waves indicating that they are not involved in triggering or supporting the peristalsis of these organs, but

variety of cell populations interacting with the TCs, many different and organspecific TCs roles are conceivable suggesting that these cells might take center stage in *the integration of the overall interstitial information* from the vascular, nervous, and immune systems, as well as from tissue-resident stem cells

proposed for the TCs located in the urinary bladder lamina propria.

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

morphogenesis.

cological interventions.

one receptors at their level.

pathologies such as the NDO.

more detailed studies are necessary.

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

*Innovations in Cell Research and Therapy*

endothelial cells [114].

myocardial fibrosis [116].

tional demands.

stromal cells

of TCs depending on their location.

staining 1 day after ISO treatment. Interestingly, treatment with grape seed extract (GSE) could significantly increase cardiac TCs numbers and enhance angiogenesis in myocardia but not in other tissues; in fact, it was found suppressing angiogenesis in tumor tissues instead [114]. Thus, GSE was regarded to promote angiogenesis by modulating cardiac TCs, which subsequently stimulated

Also, in a rat myocardial infarction model induced by coronary occlusion, cardiac TCs were reported undetectable in the infarction zone from 4 days to 4 weeks [115]. Simultaneous transplantation of cardiac TCs could significantly decrease infarct size and improve heart function 2 weeks after myocardial infarction [115]. Moreover, the protective effects of intramyocardial transplantation of cardiac TCs were also observed 14 weeks after myocardial infarction as evidenced by improved heart function, decreased infarct size, increased angiogenesis, and decreased

Currently, no single specific immunophenotype for cardiac TCs has been identified [101]. For in-depth studies of cardiac TCs, it is highly needed to identify a specific immunostaining marker for them. Most isolated cardiac TCs are either not pure enough (as cardiac fibroblasts grow much faster than cardiac TCs) or only containing subtypes of cardiac TCs. It would be beneficial to investigate the therapeutic effects of cardiac TCs or cardiac TCs-derived exosomes. Moreover, the immunoregulatory effects of cardiac TCs should be thoroughly investigated. Finally, other

In conclusion, this review of the literature data indicates that TCs, depending on their location, may display different immunohistochemical properties, ultrastructural peculiarities and form complex networks making contacts either between themselves or with other cell types. Further, our current knowledge of TCs allows the following conclusions on the role(s) that these cells may play, some of which might be common to the different organs and some be organ-/region-specific.

1.In the stromal space of all the organs taken into account, TCs appear as connecting cells. Reasonably, TCs, due to their homo- and hetero-cellular contacts, can be considered as *connecting devices* playing either common or region-specific roles. These contacts might be merely mechanical or sites of cross-talking between TCs and other cell types establishing intercellular molecular exchanges. Spatial relationships also suggest an involvement of the TCs network in the coordination of tissue homeostasis in response to local func-

The involvement in tissue homeostasis might be explained by the heterogeneity

2.TCs might be engaged in *controlling the proliferation and differentiation of the stem cells* and, either in the adulthood or during organ differentiation, wherever they are located, these cells might be considered as a pool of mesenchymal

As an example, in the gastrointestinal tract and the urinary bladder, the subepithelial plexus formed by TCs likely supports the stem cell proliferation and epithelial renewal and, the TCs located in the muscle coat, might differentiate into ICCs

organs or tissue-specific TCs are worthy to be studied.

**6. Conclusion and future overlook for telocytes' study**

**84**

and, undergoing to phenotypic changes, become a cell source of gastrointestinal stromal tumors such as GIST. A shift toward a myofibroblast phenotype has been proposed for the TCs located in the urinary bladder lamina propria.

In the female genital tract, although there are no reported interactions with stem cells, a role for TCs in this direction cannot be overlooked because neo-angiogenesis undoubtedly accompanies myometrial hypertrophy.

Moreover, in the heart, a special inter-relation exists between TCs and cardiac stem cells based on the exchange of information via extracellular vesicles which shuttle miRNA or by direct connections through typical and atypical junctions. The secretome of TCs might enhance the proliferation and differentiation of cardiac stem cells. Suggestions were also made regarding the possibility of their role in the re-activation of dormant myocardial precursors during the repair of the adult heart, while in embryo TCs act as inductors/regulators of differentiation during morphogenesis.

3.The TCs scaffold located in all the hollow organs follows organ distension and relaxation likely to avoid anomalous organ deformation and to control blood vessels closure or rheology. This is *a mechanical role* whose importance has been demonstrated in some gastrointestinal pathologies, where TCs loss provokes severe architectural derangement and contributes to the altered 3D ECM organization in the fibrotic intestinal wall. In the uterus, TCs can function as a sensor for the mechanical stress exerted on the uterine wall, allowing uniform uterine growth during pregnancy, by mechanosensitive coordination due to the existence of different ionic channels which can be modulated by pharmacological interventions.

Moreover, TCs can also be regarded as chemical sensors as it was hypothesized for the human uterus and fallopian tube, where TCs might play an important role in the uterine contraction mechanism due to the presence of estrogen and progesterone receptors at their level.

4.Because of the anatomical complexity of the hollow organs and the great variety of cell populations interacting with the TCs, many different and organspecific TCs roles are conceivable suggesting that these cells might take center stage in *the integration of the overall interstitial information* from the vascular, nervous, and immune systems, as well as from tissue-resident stem cells

In the gastrointestinal tract, a particular role is played by the intramuscular hetero-cellular TCs network in *supporting the spreading of the slow waves generated by the ICCs*, which are electrically coupled to the smooth muscle cells, thus contributing to the regulation of gastrointestinal motility. In agreement with this hypothesis is the evidence that the simultaneous reductions in the TCs and ICCs account for the intestinal dysmotility characterizing the IBD. In the urinary bladder, the sub-urothelial TCs likely play a role as intermediaries in propagating chemical or electrical stimuli locally generated being the target of the paracrine activity of the urothelium and the nervous system. 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, responses that are lost in urinary pathologies such as the NDO.

In female genital tract, TCs seems to lack in regular slow waves indicating that they are not involved in triggering or supporting the peristalsis of these organs, but more detailed studies are necessary.

Currently, for a more undoubted TCs identification and careful characterization, no single specific immunophenotype marker is adequate. Transmission electron microscope is still considered the instrument necessary for the identification of TCs with certainty. Recently, FIB-SEM tomography was used to confirm that TCs come in contact with each other thus forming networks that constitute the scaffold organizing the stromal and the parenchymal components of the organs. For in-depth studies of TCs roles, it is highly needed to find out functional markers or receptors for the specific TC subtypes and TCs functional molecules.
