**5. Conclusions**

65]. In other mammals (cats, dogs and rabbits) [26] including humans, NIC have been detected in the pancreas during prenatal development. The morphogenetic mechanisms underlying the integration between structures of the nervous system and endocrine cells remain unclear.

In his work, Van Campenhout [24] found that all primary islets (Laguesse islets) form NIC; he first suggested that the nervous system may be involved in the development of the endocrine pancreas. He proposed that NIC form through the budding of islet cells from the primitive ducts followed by their migration into adjacent neural tissue and that the differentiation of islet cells may occur under the influence of nervous components of these complexes (cited from [26]). Consequently, it was shown that both NIC and non-innervated islets can be detected in the fetal pancreas. In our studies, we also found NIC and non-innervated islets in the human

Nonetheless, genetic studies on mice have confirmed that the nervous system may regulate the differentiation of endocrine cells. In mice deficient for Phox2b or Foxd3 gene expression (Phox2b−/− or Foxd3−/−), neural crest cells and their derivatives are absent in the pancreas. It was shown that, in such mutant embryos, the total β-cell mass and β-cell proliferation had increased [66]. Furthermore, β-cells in the mutant embryos were immature, since the expression levels of MafA and Pdx1 mRNA in β-cells were decreased, and insulin granules had abnormal morphology and were decreased in number [67]. Taken together, these data demonstrate that signals from the neural crest negatively regulate β-cell proliferation and positively regulate β-cell maturation [66, 67]. Moreover, in the developing mouse pancreas, neural crest cells and their derivatives are located in close proximity to endocrine β- and αcells, suggesting that the regulation of β-cell mass and their maturation may occur through juxtacrine and paracrine signals from the nervous system [67, 68]. Similar results, demonstrating that co-culturing pancreatic islets with neural crest stem cells promotes the regeneration

A recent study has also shown an important role of sympathetic innervation in the establishment of pancreatic islet architecture and functional maturation during development. The absence of sympathetic innervation during development resulted in altered islet architecture,

Several studies have demonstrated that the structures of the nervous system interact with endocrine cells through the homophilic binding of cell adhesion molecules (NCAM and SynCAM), which are expressed on the surface of pancreatic endocrine cells and neural crestderived cells in both rodents [68, 71] and humans [72]. Contacts between forming islets and NCAM-positive nerve fibers have been observed in the human fetal pancreas [72]. Therefore, it has been proposed that autonomic nerves may facilitate the outpouching of endocrine cell clusters to form islets through the homophilic binding of CD56 (NCAM) molecules on both of

In our studies, we have demonstrated close integration between the structures of the nervous system and endocrine cells in the human pancreas, which was more frequently observed during prenatal development. We suggest that such integration may be necessary for the development of the endocrine pancreas in humans [22, 35]. It is possible that the nervous

reduced insulin secretion and impaired glucose tolerance in adult mice [70].

fetal and adult pancreas [22, 35].

10 Challenges in Pancreatic Pathology

of functional β-cells, were observed in vitro [69].

these tissues [72].

In the pancreas of many mammals, including humans, endocrine islet cells are closely integrated with the structures of the nervous system into NIC. The morphological organization of such complexes varies considerably depending on the type of cells forming the complex and their ratios. According to the most current data, the nervous system is involved in the regulation and synchronization of islet hormone secretion and the morphogenetic plasticity of the endocrine pancreas in adults. During the prenatal development of the pancreas, the nervous system regulates endocrine cell proliferation and maturation and is involved in the establishment of islet architecture. In humans, NIC are more abundant and variable in their structure during prenatal development. This fact may serve as morphological evidence of the involvement of the nervous system in the morphogenesis of the human endocrine pancreas.
