Connective tissue growth factor (CTGF)/CCN family member 2 (CCN2) is a CCN family member of matricellular signaling modulators. It has been shown that CCN2/CTGF mediates cell adhesion, aggregation and migration in a large variety of cell types, including vascular endothelial cells, fibroblasts, epithelial cells, aortic smooth muscle and also pluripotent stem cells. Others matricellular proteins are capable of interacting with CCN2/CTGF to mediate its function. Cell migration is a key feature for tumor cell invasion and metastasis. CCN2/CTGF seems to be a prognostic marker for cancer. In addition, here we intend to discuss recent discoveries and a new strategy to develop therapies against CCN2/CTGF, in order to treat cancer metastasis.

The irinotecan (CPT-11) causes intestinal mucositis and diarrhea that may be related to changes in the enteric nervous system (ENS). In inflammatory condition, mast cells release a variety of pro-inflammatory mediators that can interact with the ENS cells. It has not been explored whether CPT-11 is able to alter the enteric glial and neuronal cell, and the role of mast cells in this effect. Therefore, this study was conducted to investigate the effect of CPT-11 on the enteric glial and neuronal cells, as well as to study the role of mast cells in the CPT-11-induced intestinal mucositis. Intestinal mucositis was induced in Swiss mice by the injection of CPT-11 (60 mg/kg, i.p.) once a day for 4 days following by euthanasia on the fifth day. To investigate the role of mast cells, the mice were pretreated with compound 48/80 for 4 days (first day, 0.6 mg/kg; second day, 1.0 mg/kg; third day, 1.2 mg/kg; fourth day, 2.4 mg/kg) to induce mast cell degranulation before the CPT-11 treatment. Here, we show that CPT-11 increased glial fibrillary acidic protein (GFAP) and S100β gene and S100β protein expressions and decreased HuC/D protein expression in the small intestine segments. Concomitantly, CPT-11 enhanced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels and inducible nitric oxide synthase (iNOS) gene expression, associated with an increase in the total number macrophages (positive cells for ionized calcium-binding adapter molecule, Iba-1) and degranulated mast cells in the small intestine segments and caused significant weight loss. The pretreatment with compound 48/80, an inductor of mast cells degranulation, significantly prevented these CPT-11-induced effects. Our data suggests the participation of mast cells on the CPT-11-induced intestinal mucositis, macrophages activation, enteric reactive gliosis, and neuron loss.

The enteric glia, a neural crest-derived cell type that composes the Enteric Nervous System, is involved in controlling gut functions, including motility, gut permeability, and neuronal communication. Moreover this glial cell could to give rise to new neurons. It is believed that enteric neurons are generated up to 21 days postnatally; however, adult gut cells with glial characteristics can give rise to new enteric neurons under certain conditions. The factors that activate this capability of enteric glia to differentiate into neurons remain unknown. Here, we followed the progress of this neuronal differentiation and investigated this ability by challenging enteric glial cells with different culture conditions. We found that, in vitro, enteric glial cells from the gut of adult and neonate mice have a high capability to acquire neuronal markers and undergoing morphological changes. In a co-culture system with 3T3 fibroblasts, the number of glial cells expressing βIIItubulin decreased after 7 days. The effect of 3T3-conditioned medium on adult cells was not significant, and fewer enteric glial cells from neonate mice began the neurogenic process in this medium. Laminin, an extracellular matrix protein that is highly expressed by the niche of the enteric ganglia, seemed to have a large role in inhibiting the differentiation of enteric glia, at least in cells from the adult gut. Our results suggest that, in an in vitro approach that provides conditions more similar to those of enteric glial cells in vivo, these cells could, to some extent, retain their morphology and marker expression, with their neurogenic potential inhibited. Importantly, laminin seemed to inhibit differentiation of adult enteric glial cells. It is possible that the differentiation of enteric glia into neurons is related to severe changes in the microenvironment, leading to disruption of the basement membrane. In summary, our data indicated that the interaction between the enteric glial cells and their microenvironment molecules significantly affects the control of their behavior and functions.

Several studies have proved that glial cells, as well as neurons, play a role in pain pathophysiology. Most of these studies have focused on the contribution of central glial cells (e.g., microglia and astrocytes) to neuropathic pain. Likewise, some works have suggested that peripheral glial cells, particularly satellite glial cells (SGCs), and the crosstalk between these cells and the sensory neurons located in the peripheral ganglia, play a role in the phenomenon that leads to pain. Nonetheless, the study of SGCs may be challenging, as the validity of studying those cells in vitro is still controversial. In this study, a research protocol was developed to examine the potential use of primary mixed neuronal–glia cell cultures obtained from the trigeminal ganglion cells (TGCs) of neonate mice (P10–P12). Primary cultures were established and analyzed at 4 h, 24 h, and 48 h. To this purpose, phase contrast microscopy, immunocytochemistry with antibodies against anti-βIII-tubulin and Sk3, scanning electron microscopy, and time-lapse photography were used. The results indicated the presence of morphological changes in the cultured SGCs obtained from the TGCs. The SGCs exhibited a close relationship with neurons. They presented a round shape in the first 4 h, and a more fusiform shape at 24 h and 48 h of culture. On the other hand, neurons changed from a round shape to a more ramified shape from 4 h to 48 h. Intriguingly, the expression of SK3, a marker of the SGCs, was high in all samples at 4 h, with some cells double-staining for SK3 and βIII-tubulin. The expression of SK3 decreased at 24 h and increased again at 48 h in vitro. These results confirm the high plasticity that the SGCs may acquire in vitro. In this scenario, the authors hypothesize that, at 4 h, a group of the analyzed cells remained undifferentiated and, therefore, were double-stained for SK3 and βIII-tubulin. After 24 h, these cells started to differentiate into SCGs, which was clearer at 48 h in the culture. Mixed neuronal–glial TGC cultures might be implemented as a platform to study the plasticity and crosstalk between primary sensory neurons and SGCs, as well as its implications in the development of chronic orofacial pain.

The enteric nervous system (ENS), also known as second brain, innervates our gastrointestinal tract controlling its functions, such as motility, fluid secretion, nutrient absorption, and even involvement in the control of immunity and inflammatory processes. In the gut, the gliocytes are known as enteric glial cells (EGCs). Enteric glial cells form a network that permeates the entire gut. Enteric glia express the cell surface hemichannel of connexin-43 (Cx43) necessary for the propagation of Ca2 + responses, necessary to maintain their functions. In this chapter, besides the development of ENS and its glial cells and the similarities with the astrocytes in the central nervous system, we approached the important role of the glial network in the control of gut homeostasis, in the interaction with the immune system, and its participation in pathological conditions. EGCs are even capable of replacing lost neurons. Thus the enteric glia is a multifunctional cell, which through its multiple interactions maintains the integrity of the ENS allowing it to be resistant to the different and constant aggressions suffered by the digestive system.