Enterochromaffin (EC) cells (also known as Kulchitsky cells), are a type of enteroendocrine and neuroendocrine cell. They reside alongside epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal regulation, particularly intestinal motility and secretion. EC cells modulate neuron signalling in the enteric nervous system (ENS) via the secretion of the neurotransmitter serotonin and other peptides. As enteric afferent and efferent nerves do not protrude into the intestinal lumen EC cells act as a form of sensory transduction. Serotonin in the ENS acts in synergy with other digestive hormones to regulate sensory and motor gastrointestinal reflexes. EC cells respond to both chemical and neurological stimuli. They are also reactive to mechanosensation and can be stimulated by a bolus moving through the bowel. Upon activation, EC cells release serotonin to act upon serotonin receptors on ENS neurons. Dependent on concentration, serotonin can then modulate peristaltic contraction and secretion through activation of smooth muscle and glands respectively.
EC cells are found aggregated in specific locations throughout the gastrointestinal tract, predominately in the small intestine, colon and appendix. The proportion of high density cell populations varies between species attributed to differences in dietary requirements and physiological characteristics.
EC cells are small polygonal cells located in the crypts between intestinal villi. They are discriminated from other cells of the gastrointestinal epithelial crypts by the presence of basally-located granulations that contain serotonin and other peptides. Ultrastructurally, these granules are described to be varying in size and shape and are considered pleomorphic in nature. Most EC cells communicate with the lumen of intestinal crypts through apical microvilli protrusions and are referred to as “open”. A proportion of EC cells also present do not protrude into the crypt lumen and are subsequently referred to as ‘closed’. EC cells typically extend down to the basal lamina with cytoplasmic extensions known to pass through the connective tissue and neighbouring glands. Tissue beneath EC cells typically contains abundant fenestrated capillaries, lymph vessels and small unmyelinated nerve fibres. Secreted serotonin can either be taken up into residing vessels (transported in the blood by platelets) or act on nerve synaptic terminals.
The primary function of EC cells is to synthesise and secrete serotonin for modulation of gastrointestinal neurons. Serotonin, also named 5-Hydroxytriptamine (5HT) can be classified as a hormone, neurotransmitter and a mitogen. It is primarily known for its role in the central nervous system but plays an important role in the periphery with largest endogenous pool of serotonin residing in the gut (90% of endogenous store). In the ENS serotonin is an essential modulator of sensory transduction and mucus secretion. Release of serotonin from EC cells can be triggered by a multitude of stimuli, particularly luminal distension, parasympathetic innervation or changes in osmotic concentrations in intestinal contents.
The synthesis of 5-HT, in EC cells, is catalyzed by the enzyme tryptophan hydroxylase 1 (TpH1) from the amino acid L-tryptophan. The reaction proceeds in two stages with an initial rate limiting step involving the conversion of L-tryptophan to 5-hydroxytryptophan (5-HTP). Following conversion to 5-HTP, the non-rate limiting L-amino acid decarboxylase converts 5-HTP to 5-HT by decarboxylation. Following synthesis, 5-HT is then stored in vesicles by vesicular monoamine transporter 1 close to the basal margin of the cell for eventual secretion. Release of the vesicles occurs after chemical, neurological or mechanical stimulation of the EC cells and is predominantly calcium dependent, suggesting excretion via exocytosis. The combined effect of increased calcium flux and a liberation of stored calcium within the cell changes the cell potential triggering release of the 5-HT vesicles. The vesicles pass from the basal margin into the surrounding lamina propria for interaction with nearby nerve synapses, lymph and blood vessels. The serotonin synthesised by EC cells is predominately exocytosed from the basal border, but is also known to be apically secreted into the lumen of the gut and can be present in faecal samples. Secreted 5-HT acts on different receptor subtypes found localised in cells in the gastrointestinal epithelium, smooth muscle and connective tissue with responsiveness dependent on the concentration of the secreted hormone. The primary effect of serotonin involves the increase in peristaltic contraction through its effects on both ENS neurons and smooth muscle. 5-HT also activates a neural secretory response, whereby binding at 5-HT1P receptors on myenteric neurons triggers a signalling cascade in the submucosal plexus. This results in the release of acetylcholine to initiate secretion from the gut mucosa via release of chlorine ions.
In developing chick embryos, EC cells have been found in biopsies of developing GIT tissue before the migration of neural crest cells. Whilst EC cells have neuroendocrine properties and are similar chemically and histologically to cells of the adrenal medulla they are not derivatives of the neural crest and do not share a similar cell progenitor. EC cells are believed to be derived from endodermal origins and are descended from the stem cells that form other epithelial cell types of the gastrointestinal lumen.
Irritable bowel syndrome
Irritable bowel syndrome (IBS) is a diverse condition associated with chronic bowel discomfort and abdominal pain that ranges in severity between patients. Abnormal concentrations of serotonin have been associated with IBS, predominantly increased concentrations intensifying gastrointestinal motility and mucosal secretions from the gut mucosa. Severe IBS patients are often divided into two extremes, chronic constipation or chronic diarrhoea, abnormal EC cell populations have been correlated with both conditions. In patients suffering post-infectious IBS, rectal biopsies have shown dramatic increase in populations of EC cells associated with diarrhoeal symptoms. Likewise reduced populations of EC cells in patients suffering chronic constipation has been observed, indicating a lack of 5-HT and therefore decrease GI motility and secretion. Ongoing research indicates abnormal EC cell populations and therefore 5-HT signalling may significantly contribute to gastrointestinal dysfunction. Treatment using 5-HT-receptor agonists for patients with functional constipation have shown some effectiveness in returning normal GI functionality.
Carcinoid syndrome is a rare condition characterised by an abnormal increase in circulating biologically active hormones, largely serotonin with early symptoms involving diarrhoea, abdominal cramping and episodic flushing. Excess circulating serotonin is usually manufactured by EC-cell-originated carcinoid tumours in the small bowel or appendix. Tumours are slow growing but can metastasise to the liver if aggressive. They can also be present in other sites, particularly the lung and stomach.
The name ‘enterochromaffin’ comes from the Greek word “enteron” (ἔντερον), in relation to intestines and “chromaffin” as a grouping of the words chromium and affinity as they can be visualised by staining with chromium salts. Similarly named, Chromaffin cells (of the adrenal medulla) share this characteristic and are histologically alike to EC cells. Their embryological origins however are quite different and they do not possess similar functions.
“Enterochromaffin-like (ECL) cells” are a population of cells that are found in the gastric pits of the stomach luminal epithelium and secrete histamine. In response to gastrin released by neighbouring G-cells, secreted histamine from ECL cells acts on parietal cells to stimulate the release of gastric acid. The presence of ECL cells is critical in regulation of endocrine-induced gastric acid secretion. ECL cells histologically appear similar to EC cells and are hence named as such. They are however a different cell type and do not possess any serotonin synthesizing mechanisms.
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