Pearse and Polak formulated the neural crest theory for the origin of NE cells [23]. However, LeDouarin and Teillet could not find evidence for neural crest origin of NE cells in the gastrointestinal tract when studying chimeric birds (chicken and quail) [24] and, therefore, NE cells in the gastrointestinal tract are presumed to be of endodermal origin. Nevertheless, NE cells have important differences compared with other mucosal cells since they can proliferate [25], and some may be pluripotent [26]. 

The main regulator of the ECL cell function, that is histamine release, is gastrin. Gastrin released by food intake, has a high potency reflecting high affinity to the gastrin receptor. This is demonstrated by detectable stimulation of histamine release at a concentration of 2 pmol/L [31]. Moreover, maximal effect is reached at about 500 pmol/L, similar to the trophic effect in rats [32], and to the functional [33] and trophic [34] effects in humans. There is no threshold for the trophic effect of gastrin and, consequently, only moderate hypergastrinemia as usually seen during treatment with inhibitors of gastric acid secretion, induces ECL cell hyperplasia [35]. The increase in ECL cell mass results in increased histamine release [13], which is responsible for the rebound acid hypersecretion seen after stopping treatment with PPIs [36]. The cholinergic agent McN-A-323 (muscarinic-1 analogue) did not stimulate histamine release, whereas vagal stimulation increased histamine release in the isolated rat stomach, although not sufficiently completely explained the stimulation of acid secretion [37]. The vagal stimulation of histamine release is probably mediated by PACAP (pituitary adenylate cyclase-activating polypeptide) released from neurons [38]. Like gastrin, PACAP has a trophic effect on the ECL cell that could be responsible for the trophic effect of the vagal nerves, elegantly shown by unilateral vagotomy in rats by Håkanson and co-workers [39]. The role of PACAP in the trophic regulation of the ECL cell is, however, difficult to assess since, presently, there is no method to quantitate vagal activity. Somatostatin inhibits histamine release and, at the same time, parietal cell H+ secretion, making it a very efficient inhibitor of acid secretion [40]. Generally, there is a close relationship between functional and trophic regulation of a cell type, which is logical from a biological point of view. This is also the case for the ECL cell. Thus, gastrin not only stimulates histamine release, but also proliferation of the ECL cell, effects mediated by the same gastrin receptor and accordingly showing similar concentration dependence. Long-term hypergastrinemia leads to ECL cell hyperplasia, manifested by rebound acid hypersecretion [36] and in the long-term by ECL cell-derived tumours of variable malignancies [38]. Gastrin undoubtedly predisposes to ECL cell neuroendocrine tumours (NETs). There are also arguments for a role of gastrin in the pathogenesis of gastric carcinomas, as patients with autoimmune gastritis have increased risk of malignancy [41,42]. Moreover, patients with hypergastrinemia upon long-term follow-up have an increased prevalence of gastric cancer [43]. PACAP is probably responsible for the functional and trophic effects of the vagal nerves on the ECL cell [44]. Long-term treatment with the long-acting somatostatin analogue octreotide reduced ECL cell density in hypergastrinemic patients secondary to autoimmune gastritis [45]. Octreotide also reduced ECL cell density in hypergastrinemic rats due to dosing with a peroxisome proliferator type α, without affecting the gastrin concentration [46].