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Neuroendocrine cell
Neuroendocrine cell
Neuroendocrine cell
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Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration. An example of a neuroendocrine cell is a cell of the adrenal medulla (innermost part of the adrenal gland), which releases adrenaline to the blood. The adrenal medullary cells are controlled by the sympathetic division of the autonomic nervous system. These cells are modified postganglionic neurons. Autonomic nerve fibers lead directly to them from the central nervous system. The adrenal medullary hormones are kept in vesicles much in the same way neurotransmitters are kept in neuronal vesicles. Hormonal effects can last up to ten times longer than those of neurotransmitters.[citation needed] Sympathetic nerve fiber impulses stimulate the release of adrenal medullary hormones. In this way the sympathetic division of the autonomic nervous system and the medullary secretions function together.

The major center of neuroendocrine integration in the body is found in the hypothalamus and the pituitary gland. Here hypothalamic neurosecretory cells release factors to the blood. Some of these factors (releasing hormones), released at the hypothalamic median eminence, control the secretion of pituitary hormones, while others (the hormones oxytocin and vasopressin) are released directly into the blood.

APUD cells are considered part of the neuroendocrine system, and share many staining properties with neuroendocrine cells.

Major neuroendocrine systems

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Pulmonary neuroendocrine cells

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Pulmonary neuroendocrine cells (PNECs) are specialized airway epithelial cells that occur as solitary cells or as clusters called neuroepithelial bodies (NEBs) in the lung. Pulmonary neuroendocrine cells are also known as bronchial Kulchitsky cells.[2] They are located in the respiratory epithelium of the upper and lower respiratory tract. PNECs and NEBs exist from fetal and neonatal stages in the lung airways.

These cells are bottle- or flask-like in shape, and reach from the basement membrane to the lumen. They can be distinguished by their profile of bioactive amines and peptides, namely serotonin, calcitonin, calcitonin gene-related peptide (CGRP), chromogranin A, gastrin-releasing peptide (GRP), and cholecystokinin.

These cells can be the source of several types of lung cancer, most notably small cell carcinoma of the lung, and bronchial carcinoid tumor.[3][4]

Function

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PNECs may play a role with chemoreceptors in hypoxia detection. This is best supported by the presence of an oxygen-sensitive potassium channel coupled to an oxygen sensory protein in the rabbit lumenal membrane. They are hypothetically involved in regulating localized epithelial cell growth and regeneration through a paracrine mechanism, whereby their signaling peptides are released into the environment. In addition, they contain neuroactive substances which are released from basal cytoplasm. These substances induce autonomic nerve terminals or vasculature in the deep lamina propria.

Role in fetal lung

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In the fetal lung, they are frequently located at the branching points of airway tubules, and in humans are present by 10 weeks gestation. Peptides and amines released by PNEC are involved in normal fetal lung development including branching morphogenesis. The best-characterized peptides are GRP, the mammalian form of bombesin, and CGRP; these substances exert direct mitogenic effects on epithelial cells and exhibit many properties akin to growth factors.

Example

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Examples

Specialized groups of neuroendocrine cells can be found at the base of the third ventricle in the brain (in a region called the hypothalamus). This area controls most anterior pituitary cells and thereby regulates functions in the entire body, like responses to stress, cold, sleep, and the reproductive system. The neurons send processes to a region connecting to the pituitary stalk and releasing hormones are delivered into the bloodstream. They are carried by portal vessels to the pituitary cells where they may stimulate, inhibit, or maintain the function of a particular cell type.

See also

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References

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Neuroendocrine cell

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Neuroendocrine cells are specialized epithelial cells that exhibit both neuronal and endocrine properties, secreting hormones, neuropeptides, and bioactive amines into the bloodstream or local environments in response to neural, hormonal, or environmental stimuli. These cells, which contain dense-core secretory granules and express characteristic markers such as chromogranin A and , are dispersed throughout the body as part of the diffuse neuroendocrine system (DNES), primarily in epithelial tissues of organs like the , lungs, , and . Originating mostly from endodermal progenitors during embryonic development, they play a crucial role in sensing physiological changes and maintaining by bridging the nervous, endocrine, and immune systems. The concept of the DNES was first proposed by Friedrich Feyrter in 1938, building on earlier observations of enterochromaffin cells in the gut from the late , and was further refined by A.G.E. Pearse in the through the APUD (amine precursor uptake and ) theory, which highlighted their shared biochemical traits. Neuroendocrine cells are typically found as solitary units or small clusters (neuroepithelial bodies) within mucosal linings, often innervated by autonomic nerves that trigger their release of substances like serotonin, , calcitonin, or insulin. Their nuclei display a distinctive "salt-and-pepper" pattern, and they are regulated by transcription factors such as ASCL1, NEUROG3, and INSM1, which drive their differentiation and plasticity. This plasticity allows neuroendocrine cells to adapt to stress or injury, sometimes serving as stem-like progenitors in tissues like the . Functionally, neuroendocrine cells act as chemosensors and effectors, detecting stimuli such as hypoxia, changes, or luminal contents to modulate processes including blood flow, , , and immune responses. For instance, pulmonary neuroendocrine cells sense oxygen levels to regulate , while gastrointestinal counterparts influence and via peptides like or cholecystokinin. They contribute to systemic circuits, such as the hypothalamic-pituitary-adrenal (HPA) axis for stress responses or the vagus nerve-mediated inflammatory reflex to control release. Dysregulation of these cells can lead to neuroendocrine neoplasms, which account for about 2% of cancers and may cause hormonal syndromes due to excess . Recent advances, including , have revealed their evolutionary conservation from early metazoans and epigenetic mechanisms underlying their role in both health and disease.

Overview

Definition

Neuroendocrine cells are specialized cells that integrate neural and endocrine functions, receiving input from the —typically through synaptic connections or paracrine signals—and responding by secreting hormones, bioactive peptides, or amines directly into the bloodstream or local tissue environments. This dual capability distinguishes them from purely neural cells, which primarily transmit electrical signals, or conventional endocrine cells, which release hormones in response to humoral or direct stimuli without direct neural innervation. A hallmark of neuroendocrine cells is their expression of molecular markers reflective of this integrated phenotype, including neuronal proteins such as , which is associated with synaptic vesicles, and endocrine markers like chromogranin A, a component of secretory granules. These markers enable identification through and underscore the cells' ability to process neuronal signals for regulated release. The term "neuroendocrine" derives from the Greek roots "neuro-" (referring to nerve or neural input) and "endocrine" (meaning internal secretion), compounded in English to describe this hybrid functionality, with its earliest documented use appearing in 1922. Evolutionarily, neuroendocrine cells trace their origins to ancient sensory-secretory prototypes, present in primitive such as coelenterates and conserved across bilaterian animals, including vertebrates, indicating a deep-rooted role in coordinating environmental responses with hormonal output.

Historical Development

The discovery of neuroendocrine cells traces back to the late , when early histological observations identified specialized cells within the . In 1870, Rudolf Heidenhain described chromaffin cells in the of rabbits and dogs, noting their affinity for salts and potential role in , marking one of the first recognitions of endocrine-like elements outside organized glands. Building on this, Nikolai Kulchitsky in 1897 provided a detailed description of enterochromaffin cells in the intestinal mucosa of cats and dogs, characterizing them as basally located cells with granular that stained with silver and , and suggesting their involvement in local regulatory functions. In the 1930s, Friedrich Feyrter advanced the understanding by proposing the concept of a "diffuse endocrine system," identifying pale-staining "clear cells" (Helle Zellen) scattered throughout epithelial and connective tissues, including the and gut, using Masson's . Feyrter viewed these cells as paracrine elements distinct from classical endocrine glands, capable of influencing neighboring tissues through release, and likened their distribution to a neuroendothelial network. The advent of electron microscopy in the mid-20th century further confirmed their neuroendocrine , revealing characteristic dense-core secretory granules—electron-dense structures 100-300 nm in —within these cells, providing ultrastructural evidence of their capacity for and storage and release, as observed in studies from the 1960s onward. The brought a unifying framework with A.G.E. Pearse's introduction of the APUD (amine precursor uptake and ) concept in 1966-1969, grouping Feyrter's clear cells and other dispersed endocrine elements into a series based on their shared ability to uptake amine precursors like 5-hydroxytryptophan and decarboxylate them into bioactive amines, alongside production of polypeptide hormones. This idea refined the diffuse neuroendocrine system (DNES) during the and , distinguishing it from organized endocrine glands like the pituitary or , and emphasizing its widespread distribution across gut, , and other sites as a paracrine regulatory network. By the and , the APUD faced significant critique, primarily due to inconsistencies in expression—not all purported APUD cells uniformly demonstrated uptake and —and erroneous assumptions about their embryonic origin from the . Experimental evidence, including studies in embryos by Pictet et al. (1972) showing intact pancreatic endocrine cells without neural crest contribution, and quail-chick chimeras by Le Douarin and Fontaine (1970s-1980s) demonstrating endodermal derivation for gut and pancreatic cells, led to its abandonment. This shift paved the way for modern classifications relying on specific immunohistochemical markers rather than the APUD rubric, acknowledging diverse ontogenies while retaining the DNES as a functional concept.

Cellular Characteristics

Morphology and Ultrastructure

Neuroendocrine cells exhibit a distinctive morphology that reflects their dual epithelial and neural-like properties, typically appearing as flask-shaped or pyramidal cells integrated within epithelial layers. These cells demonstrate cellular polarity, with secretory granules concentrated at the basal pole for hormone release toward the or . In open-type cells, the apical surface features microvilli that extend into the lumen, facilitating direct chemosensory detection of luminal contents such as nutrients or changes. At the ultrastructural level, electron microscopy reveals dense-core secretory granules as a hallmark feature, with diameters ranging from 100 to 300 nm. These granules consist of an electron-dense core, often eccentric and surrounded by a clear halo, enclosing hormones, biogenic amines, or chromogranins for regulated . Neuroendocrine cells also contain smaller synaptic-like clear vesicles, approximately 40-80 nm in size, clustered near the plasma membrane to enable rapid release akin to neuronal synapses. Additionally, elongated dendritic-like processes extend from the cell body, providing sites for synaptic input and integrating neural signals with secretory responses. A key morphological variation distinguishes open-type from closed-type neuroendocrine cells. Open-type cells maintain direct luminal contact via apical extensions, allowing immediate environmental sensing and rapid secretory activation, while closed-type cells are sequestered from the lumen, relying on basal or paracrine cues for stimulation and exhibiting more indirect signaling roles. This dichotomy supports their functional adaptability across tissues. Visualization of these features relies heavily on advanced imaging techniques. provides high-resolution details of granule morphology, vesicle docking, and process architecture, often complemented by immunogold labeling to localize specific proteins within structures. further confirms ultrastructural observations by detecting granule-associated markers, enhancing diagnostic precision without altering the focus on visible cellular architecture.

Molecular and Genetic Markers

Neuroendocrine cells are distinguished by key protein markers associated with their secretory granules and vesicles. Chromogranin A and B serve as major soluble components of the dense-core granule matrix, facilitating the packaging, stabilization, and regulated of hormones and neuropeptides in these cells. , an integral membrane glycoprotein, is localized to the surface of small synaptic-like microvesicles, marking the neuroendocrine vesicular apparatus. Neuron-specific (NSE), a gamma of the glycolytic , is expressed in the of neuroendocrine cells and neurons, providing a broad indicator of neuroendocrine differentiation. In addition to structural proteins, neuroendocrine cells exhibit subtype-specific expression of hormones and peptides that reflect their functional diversity. Enterochromaffin cells, for example, produce serotonin, which contributes to gastrointestinal motility regulation. is secreted by D cells to inhibit neighboring endocrine secretions, by G cells to stimulate production, and calcitonin by thyroid C cells to modulate calcium . These peptide expressions vary by anatomical location and cell type, underscoring the heterogeneity within the neuroendocrine system. At the genetic level, transcription factors such as ASCL1, NEUROG3, INSM1, ISL1, and PAX6 are essential for the differentiation and specification of neuroendocrine cells. ASCL1 drives proneural differentiation particularly in pulmonary neuroendocrine cells, NEUROG3 specifies endocrine progenitors in the gastrointestinal and pancreatic lineages, and INSM1 promotes neuroendocrine gene expression across tissues, while ISL1 and PAX6 are crucial for maturation and function in pancreatic and intestinal endocrine cells. Mutations in the MEN1 gene, which encodes the nuclear protein menin, are linked to neuroendocrine cell hyperplasia, as seen in multiple endocrine neoplasia type 1 syndrome, where loss of menin function disrupts normal cellular proliferation control in affected tissues. These molecular and genetic markers hold significant diagnostic utility, particularly through immunohistochemical staining of biopsies, where antibodies against chromogranin A, synaptophysin, and NSE reliably confirm neuroendocrine cell identity and aid in distinguishing them from other cell types based on their expression profiles.

Distribution and Classification

Gastrointestinal Tract

Neuroendocrine cells in the gastrointestinal tract, primarily known as enteroendocrine cells (EECs), are specialized epithelial cells that sense luminal nutrients and secrete hormones to regulate digestion, motility, and systemic metabolism. These cells are scattered as solitary units throughout the mucosal epithelium, extending from the esophagus to the rectum, and constitute approximately 1% of the total epithelial cell population. Their open-type morphology allows direct exposure to the gut lumen via apical microvilli, enabling rapid detection of dietary components such as carbohydrates, proteins, and fats. EECs are classified into multiple subtypes based on the predominant hormones they produce, with regional specialization along the gut axis. In the , G-cells secrete to stimulate production and enhance , while D-cells release to inhibit secretion and thereby modulate acid output. In the distal and colon, L-cells produce (GLP-1) and (PYY), which promote insulin secretion from pancreatic beta cells and suppress appetite, respectively. Other notable subtypes include K-cells in the that secrete glucose-dependent insulinotropic polypeptide (GIP) to augment postprandial insulin release. Enterochromaffin cells, the most abundant EEC subtype, release serotonin to influence and mucosal secretion. These cells play a pivotal role in nutrient sensing, integrating luminal signals to coordinate gastrointestinal responses. For instance, L-cells detect glucose through the sodium-glucose cotransporter 1 (SGLT1) on their apical surface, triggering calcium influx and exocytosis to modulate gut and enhance insulin . This sensing mechanism ensures adaptive of digestion, such as slowing gastric emptying in response to high-fat meals via cholecystokinin release from I-cells. Overall, EEC-derived hormones fine-tune absorption, , and gut-brain signaling without directly participating in epithelial barrier functions. During fetal development, EECs emerge early in the gut , around the 8th to 10th week of in humans, driven by transcription factors like Neurogenin 3 (Neurog3). Their timely differentiation influences gastrointestinal organ maturation by promoting vascularization and epithelial folding through paracrine signals, such as serotonin from nascent enterochromaffin cells. This developmental process establishes the foundational endocrine network essential for postnatal digestive regulation.

Respiratory System

Pulmonary neuroendocrine cells (PNECs) represent a distinct subtype of epithelial cells in the , characterized by their dual neuronal and endocrine features, and they primarily occur as solitary cells or in innervated clusters forming neuroepithelial bodies (NEBs) of 5–20 cells each. NEBs are densely innervated by vagal afferent nerves, enabling rapid signaling to the . These cells are distributed throughout the airway , from the trachea to the intrapulmonary bronchioles, constituting less than 0.5% of total epithelial cells, with NEBs preferentially located at branching points or bifurcations for optimal . PNECs are absent from the alveolar region and are more abundant in fetal and neonatal lungs compared to adults. PNECs function as intrapulmonary chemosensors, detecting changes in oxygen levels through an NADPH oxidase-coupled oxygen-sensitive mechanism, as well as and variations via associated ion channels. In response to hypoxia or mechanical stretch, they release serotonin (5-HT), which promotes and hypoxic pulmonary to optimize ventilation-perfusion matching. During fetal development, PNECs are among the first epithelial cells to differentiate in the pseudoglandular stage of , proliferating under the regulation of Ascl1/Notch signaling to form NEBs and contribute to airway branching and epithelial maturation. In congenital defects such as (CDH), PNEC hyperplasia occurs, likely due to disrupted Notch signaling, which may impair normal lung expansion and contribute to .

Endocrine Glands and Other Sites

Neuroendocrine cells are integral components of several organized endocrine glands, where they form clusters that enable coordinated hormonal secretion into the systemic circulation. In the of Langerhans, alpha cells produce to elevate blood glucose levels during , beta cells secrete insulin to promote glucose uptake and storage, and delta cells release to inhibit both insulin and secretion, thereby fine-tuning glucose . These islet cells receive neural modulation from intrapancreatic ganglia and autonomic nerves, which integrate signals from the to adjust release in response to metabolic demands. The thyroid gland contains C-cells, also known as parafollicular cells, which are neuroendocrine cells specialized for calcitonin production. Calcitonin secretion is triggered by elevated serum calcium levels, acting to lower calcium by inhibiting and promoting renal calcium excretion, thus contributing to calcium homeostasis. These cells originate from the and exhibit typical neuroendocrine features, including dense-core secretory granules for storage. In the adrenal medulla, chromaffin cells represent a prominent population of neuroendocrine cells that synthesize and release catecholamines, primarily epinephrine and norepinephrine, in response to sympathetic . This rapid hormonal output supports the by increasing heart rate, blood pressure, and energy mobilization. Chromaffin cells derive from progenitors and form synapses with preganglionic sympathetic neurons, underscoring their dual neural-endocrine nature. Certain cells in the exhibit neuroendocrine characteristics through dual inputs, receiving hormonal signals from hypothalamic neurons via releasing hormones delivered through the that stimulate endocrine secretion from cells. For instance, hypothalamic neurohormones like act on pituitary thyrotrophs to regulate release, integrating neural regulation with systemic endocrine output. This hypothalamic-pituitary axis exemplifies the neuroendocrine interface in the pituitary. Beyond classical endocrine glands, neuroendocrine cells appear in specialized sites such as the , where glomus cells function as oxygen sensors. These cells detect arterial hypoxia and release neurotransmitters to activate afferent nerves, eliciting ventilatory reflexes to restore oxygen levels. Glomus cells possess oxygen-sensitive ion channels and dense-core granules typical of neuroendocrine cells. Rare locations further illustrate the diffuse presence of neuroendocrine cells. In the skin, Merkel cells serve as mechanoreceptors with neuroendocrine , expressing neuropeptides and forming synaptic contacts with sensory neurons to encode light touch sensations. In the heart, atrial cardiomyocytes contain secretory granules that store and release in response to stretch, enabling the heart to function as an endocrine organ regulating and pressure. These examples highlight the widespread integration of neuroendocrine and endocrine elements across tissues for sensory and regulatory functions.

Physiological Functions

Secretion and Signaling Mechanisms

Neuroendocrine cells release hormones, neuropeptides, and neurotransmitters through regulated , a process involving the fusion of dense-core secretory granules with the plasma membrane. This fusion is calcium-dependent and typically triggered by membrane from neural or sensory inputs, which opens voltage-gated calcium channels and elevates intracellular calcium levels. The rise in calcium binds to synaptotagmin on the granule membrane, facilitating the assembly of the SNARE complex—comprising syntaxin-1, SNAP-25 on the plasma membrane, and VAMP2 on the granule—to drive bilayer fusion and content release. modes include kiss-and-run (transient pore for small molecules), cavicapture (partial protein release), and full fusion (complete granule collapse), with the latter predominant for hormones. Signaling pathways in neuroendocrine cells are initiated by diverse receptors, prominently G-protein coupled receptors (GPCRs) that detect stimuli such as tastants in enteroendocrine cells of the gut. Gs-coupled GPCRs activate to produce cAMP, which stimulates (PKA) and promotes events leading to enhanced secretion; Gq-coupled GPCRs generate diacylglycerol (DAG) and (IP3) via , activating (PKC) and releasing intracellular calcium stores to further trigger . Autocrine and paracrine loops amplify or fine-tune this process, as secreted peptides like bind to GPCRs on the same or adjacent cells, often inhibiting adenylate cyclase via Gi proteins to reduce cAMP levels and suppress release. These local signaling circuits ensure precise control over secretory output. Integration of classical neurotransmitters modulates neuroendocrine secretion, distinguishing it from purely endocrine cells. Excitatory inputs via ionotropic receptors depolarize the cell to initiate calcium influx and , while inputs through GABAA receptors hyperpolarize the membrane, inhibiting release; metabotropic glutamate and GABA receptors further modulate via GPCR pathways. This synaptic-like integration allows neuroendocrine cells to respond dynamically to signals. Regulatory factors maintain secretory through from target , such as inhibiting CRH and ACTH release in the hypothalamic-pituitary-adrenal axis, and circadian influences that impose rhythmic patterns on secretion via clock gene oscillations in neuroendocrine cells. For instance, the coordinates daily peaks in release, like from pinealocytes, ensuring temporal alignment with environmental cues. These mechanisms prevent overstimulation and synchronize physiological processes.

Role in Homeostasis and Regulation

Neuroendocrine cells are integral to systemic regulation, bridging sensory inputs and hormonal outputs to maintain physiological balance across organs. In the gut-liver axis, enteroendocrine cells in the intestinal mucosa secrete incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in response to nutrient ingestion, enhancing insulin release from pancreatic β-cells and inhibiting glucagon secretion to promote postprandial glucose disposal and hepatic glucose uptake. This mechanism accounts for over 50% of the insulin response to oral glucose, preventing hyperglycemia and supporting metabolic homeostasis. Similarly, in the respiratory system, pulmonary neuroendocrine cells (PNECs) sense local hypoxia and release bioactive peptides, including serotonin and calcitonin gene-related peptide, to modulate pulmonary vasoconstriction and optimize ventilation-perfusion matching, thereby maximizing oxygen transfer efficiency. These cells also function as environmental chemoreceptors, linking external stimuli to broader endocrine adaptations. For example, type I glomus cells in the , which exhibit neuroendocrine characteristics, detect arterial hypoxia and activate afferent nerves to the , triggering ventilatory increases and stimulating (EPO) production in the kidneys to boost formation and oxygen-carrying capacity. This sensory-endocrine integration ensures rapid homeostatic adjustments to oxygen deprivation, with EPO receptors on cells further amplifying the hypoxic response. In adaptive responses, neuroendocrine cells mediate stress modulation and developmental processes essential for . Adrenal , innervated by preganglionic sympathetic neurons, release catecholamines (epinephrine and norepinephrine) during acute stress, elevating , , and blood glucose to mobilize energy reserves and counteract threats. This "fight-or-flight" activation restores equilibrium by integrating neural signals with hormonal output, with secretion tightly regulated by calcium-dependent . During development, PNECs contribute to lung by secreting bombesin-like peptides, such as , which bind mesenchymal receptors to stimulate epithelial branching and cellular proliferation, establishing airway architecture. Beyond metabolic and respiratory , neuroendocrine cells contribute to immune through neuro-immune interactions. For instance, PNECs act as airway sensors that release neuropeptides like (CGRP) and gamma-aminobutyric acid (GABA) in response to threats, eliciting innate immune responses by activating nearby immune cells such as macrophages and promoting defenses while suppressing excessive . Similarly, in the , enteroendocrine cells secrete peptides that modulate mucosal immunity, influencing T cell activity and barrier integrity to maintain tolerance and combat pathogens. These interactions ensure coordinated responses to maintain tissue . Neuroendocrine cells also initiate protective reflexes in the upper airways. As of , studies have shown that tracheal and laryngeal neuroendocrine cells detect inhaled irritants, such as allergens or pathogens, and trigger rapid behavioral responses including and via neuropeptide signaling to sensory neurons, thereby preventing aspiration and protecting respiratory integrity. Inter-system coordination involves bidirectional interactions between neuroendocrine cells and the to fine-tune reflexes. In the , enteroendocrine cells release peptides that with enteric neurons, modulating digestive motility and secretion in response to meals, while pancreatic cells integrate parasympathetic inputs to balance insulin and for nutrient absorption. Sympathetic activation of adrenal chromaffin cells similarly amplifies these reflexes during stress, suppressing to prioritize functions and maintaining overall autonomic-endocrine harmony.

Pathophysiology and Clinical Relevance

Associated Disorders

Neuroendocrine cells play critical roles in various physiological processes, and their dysfunction contributes to several non-neoplastic disorders characterized by , hypofunction, congenital abnormalities, and inflammatory alterations. These conditions highlight disruptions in neuroendocrine signaling and secretion without . In hyperplasia syndromes, dysregulation leads to excessive proliferation or activity of neuroendocrine cells, impairing organ function. In the context of , affects pancreatic neuroendocrine cells, particularly those producing (PP cells), resulting in subnormal PP responses to and contributing to broader dysfunction. Additionally, chronic hyperglycemia in diabetes promotes within , exacerbating dysregulation and . Hypofunction of neuroendocrine cells often stems from autoimmune or degenerative processes, leading to deficient hormone secretion. In , autoimmune destruction targets insulin-producing s, which are specialized neuroendocrine cells in the , resulting in progressive loss of insulin secretion and . This T-cell-mediated attack on s is a hallmark of the disease, with autoantibodies against islet antigens like GAD65 and IA-2 facilitating demise. The resulting insulin deficiency disrupts glucose , underscoring the neuroendocrine origin of this endocrine failure. Congenital disorders involving neuroendocrine cell abnormalities manifest as structural or functional deficits from early development. features aganglionosis in the distal bowel due to absence of enteric ganglia, but enteroendocrine cells (EECs) in the aganglionic segments exhibit increased density of subtypes storing chromogranin A, serotonin, , and , suggesting compensatory rather than absence, which contributes to dysmotility and . Persistent pulmonary hypertension of the newborn (PPHN) arises from failed pulmonary vascular transition post-birth, with fetal pulmonary neuroendocrine cell (PNEC) dysregulation implicated through hypoxia-induced release of serotonin and neuropeptides like bombesin, promoting and elevated pulmonary . Inflammatory conditions link neuroendocrine cell alterations to barrier dysfunction and immune responses. In asthma, increased PNEC numbers in airways amplify allergic responses via neuropeptide secretion, with serotonin release from PNECs contributing to bronchoconstriction, mucus hypersecretion, and inflammation, exacerbating bronchospasm. In inflammatory bowel disease (IBD), EEC deficiencies impair intestinal barrier integrity, leading to heightened permeability and inflammatory signatures in organoid models; supplementation with EEC hormones like peptide YY and somatostatin restores transepithelial resistance, indicating their protective role against epithelial leaks in colitis. These changes highlight how EEC alterations disrupt mucosal homeostasis in IBD.

Neuroendocrine Tumors

Neuroendocrine tumors (NETs) arise from the neoplastic proliferation of neuroendocrine cells and are classified by the (WHO) into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs), with grading for NETs ranging from G1 to G3 based on proliferative activity assessed via mitotic count and Ki-67 labeling index. G1 tumors exhibit low proliferation with fewer than 2 mitoses per 2 mm² and Ki-67 index below 3%, indicating indolent behavior; G2 shows intermediate proliferation with 2-20 mitoses per 2 mm² or Ki-67 of 3-20%; and G3 NETs have high proliferation exceeding 20 mitoses per 2 mm² or Ki-67 above 20%, yet retain well-differentiated morphology distinct from the aggressive, poorly differentiated G3 NECs. Additionally, NETs are categorized as functional if they secrete hormones causing clinical syndromes, such as insulinomas producing excess insulin leading to , or non-functional if they lack significant hormone output and present with mass effects or metastases. This dual classification guides prognosis and management, with functional tumors often requiring targeted symptom control alongside tumor-directed therapies. Common types of NETs reflect their sites of origin, with gastrointestinal NETs (formerly termed carcinoids) being the most frequent, often arising in the , appendix, or and characterized by indolent growth but potential for from serotonin secretion. Pulmonary NETs include typical and atypical carcinoids as well-differentiated forms, while lung cancer represents a highly aggressive NEC subtype with rapid dissemination. Pancreatic neuroendocrine neoplasms (pNENs) encompass both functional variants like gastrinomas causing Zollinger-Ellison syndrome and non-functional tumors that dominate clinically due to their silent progression. , originating from skin neuroendocrine cells, is a rare but aggressive NEC variant linked to polyomavirus infection and UV exposure, often presenting as rapidly growing cutaneous nodules with high metastatic potential. Pathogenesis of NETs involves somatic mutations and stepwise progression, such as in pancreatic cases where DAXX and gene alterations occur in up to 43% of sporadic tumors, leading to alternative lengthening of telomeres and associated with poorer and higher metastatic risk. Many NETs evolve from precursor neuroendocrine cell , as seen in diffuse idiopathic pulmonary neuroendocrine cell progressing to tumors in approximately 50% of cases or gastric advancing to type 1 NETs. Paraneoplastic syndromes arise from ectopic hormone production, exemplified by due to ACTH secretion from pulmonary carcinomas or pancreatic NETs, resulting in hypercortisolism and metabolic disturbances. Diagnosis relies on somatostatin receptor imaging, particularly gallium-68 (PET), which demonstrates high sensitivity (over 90%) for detecting well-differentiated NETs by targeting overexpression, outperforming conventional imaging in staging and identifying occult metastases. Treatment strategies are tailored by grade and functionality; analogs like provide first-line control of hormone hypersecretion in functional NETs and exhibit antiproliferative effects in G1/G2 tumors, improving by up to 14 months in advanced gastroenteropancreatic NETs. For -positive advanced disease, peptide receptor radionuclide therapy (PRRT) using lutetium-177 delivers targeted radiation, achieving objective response rates of 18-30% and extending to 28 months compared to 8 months with high-dose . High-grade G3 NECs typically require platinum-based such as cisplatin-etoposide, yielding response rates of 40-70% but shorter durations due to rapid relapse. Prognostically, 5-year survival for localized gastrointestinal NETs exceeds 90-97%, contrasting with 13-54% for advanced or poorly differentiated cases, underscoring the impact of early detection and multimodal approaches.

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