Goblet cell

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Goblet cell
404 Goblet Cell new.jpg
Schematic illustration of a goblet cell in close up, illustrating different internal structures of the cell.
Gray1060.png
Transverse section of a villus, from the human intestine. X 350.
a. Basement membrane, here somewhat shrunken away from the epithelium.
b. Lacteal.
c. Columnar epithelium.
d. Its striated border.
e. Goblet cells.
f. Leucocytes in epithelium.
f’. Leucocytes below epithelium.
g. Blood vessels.
h. Muscle cells cut across.
Details
System Respiratory system
Shape Simple columnar
Function Mucin-producing epithelial cells
Identifiers
Latin exocrimohsinoctus caliciformis
MeSH D020397
TH H3.04.03.0.00009, H3.04.03.0.00016, H3.05.00.0.00006
FMA 13148
Anatomical terms of microanatomy

Goblet cells are simple columnar epithelial cells that secrete gel-forming mucins, like mucin 2 in the lower gastrointestinal tract, and mucin 5AC in the respiratory tract. [1] The goblet cells mainly use the merocrine method of secretion, secreting vesicles into a duct, but may use apocrine methods, budding off their secretions, when under stress. [2] The term goblet refers to the cell's goblet-like shape. The apical portion is shaped like a cup, as it is distended by abundant mucus laden granules; its basal portion lacks these granules and is shaped like a stem.

Contents

The goblet cell is highly polarized with the nucleus and other organelles concentrated at the base of the cell and secretory granules containing mucin, at the apical surface. [1] The apical plasma membrane projects short microvilli to give an increased surface area for secretion. [3]

Goblet cells are typically found in the respiratory, reproductive and lower gastrointestinal tract and are surrounded by other columnar cells. [1] Biased differentiation of airway basal cells in the respiratory epithelium, into goblet cells plays a key role in the excessive mucus production, known as mucus hypersecretion seen in many respiratory diseases, including chronic bronchitis, and asthma. [4] [5]

Structure

Goblet cells are found scattered among the epithelial lining of organs, such as the intestinal and respiratory tracts. [6] They are found inside the trachea, bronchi, and larger bronchioles in the respiratory tract, small intestines, the large intestine, and conjunctiva in the upper eyelid. In the conjunctiva goblet cells are a source of mucin in tears and they also secrete different types of mucins onto the ocular surface. In the lacrimal glands, mucus is synthesized by acinar cells instead. [7]

Microanatomy

Goblet cells are simple columnar epithelial cells, having a height of four times that of their width. The cytoplasm of goblet cells tends to be displaced toward the basal end of the cell body by the large mucin granules, which accumulate near the apical surface of the cell along the Golgi apparatus, which lies between the granules and the nucleus. This gives the basal part of the cell a basophilic staining because of nucleic acids within the nucleus and rough endoplasmic reticulum staining with hematoxylin. Mucin within the granules stains pale in routine histology sections, primarily because these carbohydrate-rich proteins are washed out in the preparation of microscopy samples. However, they stain easily with the PAS staining method, which colours them magenta. [8] [9]

In mucicarmine stains, deep red mucin is found within goblet cell bodies. Goblet cells can be seen in the examples below as the larger, more pale cells.

Function

The main role of goblet cells is to secrete mucus in order to protect the mucous membranes where they are found. Goblet cells accomplish this by secreting mucins, large glycoproteins formed mostly by carbohydrates. The gel-like properties of mucins are given by its glycans (bound carbohydrates) attracting relatively large quantities of water. [10] On the inner surface of the human intestine, it forms a 200 µm thick layer (less in other animals) that lubricates and protects the wall of the organ. [11]

Distinct forms of mucin are produced in different organs: while MUC2 is prevalent in the intestine, MUC5AC and MUC5B are the main forms found in the human airway. [12] In the airway, mucus is swept by the cilia of the respiratory epithelium, in a process called mucociliary clearance, and propelled out of the lungs and into the pharynx, which results in the removal of debris and pathogens from the airway. [13] MUC5AC is overexpressed in hypersensitivity pneumonitis. [13]

Mucins are continuously made and secreted by goblet cells in order to repair and replace the existing mucus layer. [13]  Mucins are stored in granules inside the goblet cells before being released to the lumen of the organ. [10] Mucin secretion in the airway may occur via regulated secretion. [14]  Secretion may be stimulated by irritants such as dust and smoke, especially in the airway. [12] Other stimuli are microbes such as viruses and bacteria.

Anomalies in the number of goblet cells are associated with changes in the secretion of mucins, which can result in many of the abnormalities seen in asthma patients, such as clogged airways due to mucus hypersecretion, and eventual loss of lung function. [13] Overexpression of MUC5AC alone does not result in the pathophysiology seen in asthma patients; it is the excessive production along with the speed of secretion that leads to the formation of thick mucus that cannot be removed by cilia or coughing action. [13] This, in addition to airway narrowing leads to the clogging of the airways, which can be detrimental to health if not treated. [13]  

There are other cells that secrete mucus (such as the foveolar cells of the stomach) [15] but these are distinguished histologically from goblet cells.

Role in oral tolerance

Oral tolerance is the process by which the immune system is prevented from responding to antigen derived from food products, as peptides from food may pass into the bloodstream via the gut, which would in theory lead to an immune response. A paper published in Nature in 2012 has shed some light on the process and implicated goblet cells as having a role in the process. [16] It was known that CD103-expressing dendritic cells of the lamina propria had a role to play in the induction of oral tolerance (potentially by inducing the differentiation of regulatory T cells), and this paper suggests that the goblet cells act to preferentially deliver antigen to these CD103+ dendritic cells. [16]

Clinical significance

Allergic asthma

The excessive mucus production seen in allergic asthma patients is due to goblet cell metaplasia, the differentiation of airway epithelial cells into mucin producing goblet cells. [17] These cells produce the thick mucins MUC5AC and MUC5B, which clog the airway, leading to the airflow obstruction characteristic of asthma. [17]

Goblet cell metaplasia in allergic asthma is due to the action of the cytokine IL-13. IL-13 binds to the IL-4Rα receptor and initiates a STAT6 signalling response. [18] Binding of IL-13 causes phosphorylation of tyrosine residues at the IL-4Rα. [18] This results in docking of STAT6 monomers, which themselves are phosphorylated and then subsequently leave the receptor and congregate form STAT6 homodimers in the cytoplasm. [18] These homodimers then enter the nucleus, where they bind to regulatory elements in the DNA, which affects the transcription of certain genes involved in mucus production. [18]

Induction of STAT6 signaling by IL-13 leads to increased of expression of 15-lipoxygenase (15-LO-1), which is an enzyme involved in the breakdown of unsaturated fatty acids. [19] 15-lipoxygenase acts by binding to phospholipids and yields hydroperoxy and epoxy metabolites. [19] One such metabolite, 15-hydroxyeicosatetranoic acid (15-HETE), is released intracellularly, where it conjugates to phosphatidylethanolamine, a phospholipid component. [19] 15-HETE-PE induces expression of the mucin MUC5AC. [19]

Goblet cell carcinoids

Goblet cell carcinoids are a class of rare tumors that form as a result of an excessive proliferation of both goblet and neuroendocrine cells. The majority of these tumors arise in the appendix and may present symptoms similar to the much more common acute appendicitis. [20] The main treatment for localized goblet cells tumors is removal of the appendix, and sometimes removal of the right hemicolon is also performed. [21] Disseminated tumors may require treatment with chemotherapy in addition to surgery. [20]

Metaplasia

Incomplete intestinal metaplasia (incomplete Barrett's esophagus), showing both foveolar cells and goblet cells, latter indicated by arrows, and usually having a slightly bluish color compared to the apical cytoplasm of foveolar cells on H&E stain. Histopathology of goblet cells (annotated) and foveolar cells in incomplete Barrett's esophagus.jpg
Incomplete intestinal metaplasia (incomplete Barrett's esophagus), showing both foveolar cells and goblet cells, latter indicated by arrows, and usually having a slightly bluish color compared to the apical cytoplasm of foveolar cells on H&E stain.

Barrett's esophagus is a metaplasia of the esophagus into intestinal epithelium, characterized by the presence of goblet cells. [22]

Treatments

Monoclonal antibodies

Studies of mice given monoclonal antibodies for IL-13 results in decreased expression of goblet cells in asthma patients. [23] Some treatments that use anti-IL-13 monoclonal antibodies include tralokinumab, and lebrikizumab. [23] These treatments have shown improvements in asthma patients, yet there are still limitations to the use of anti-IL-13 monoclonal antibodies. [23] Dupilumab is a newer drug that targets the shared receptor of IL-4 and IL-13, IL4Rα. [23] Since IL-4 and IL-13 have interrelated biological activities, Dupilumab is a more effective form of treatment as it targets both interleukins. [23]

History

The cells were first noted by Henle in 1837 when studying the lining of the small intestine, seen to be mucus producing by Leydig in 1857 (who was examining the epidermis of fish), and were given their name by Schulze in 1867, [24] [25] Schulze chose the descriptive name "goblet" because of the shape of the cell, rather than a functional name, as he remained uncertain as to the mucus-producing function of the cell. [25]

Nowadays these cells are used in the laboratories to evaluate the intestinal absorption of drug targets with different kits, such as the CacoGoblet. [26]

See also

Related Research Articles

<span class="mw-page-title-main">Barrett's esophagus</span> Premalignant condition affecting the esophagus

Barrett's esophagus is a condition in which there is an abnormal (metaplastic) change in the mucosal cells lining the lower portion of the esophagus, from stratified squamous epithelium to simple columnar epithelium with interspersed goblet cells that are normally present only in the small intestine and large intestine. This change is considered to be a premalignant condition because of its potential to further transition to esophageal adenocarcinoma, an often-deadly cancer.

<span class="mw-page-title-main">Eosinophil</span> Variety of white blood cells

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply.

<span class="mw-page-title-main">Respiratory tract</span> Organs involved in transmission of air to and from the point where gases diffuse into tissue

The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa.

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body.

<span class="mw-page-title-main">Mucus</span> Secretion produced by mucous membranes

Mucus is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It is a viscous colloid containing inorganic salts, antimicrobial enzymes, immunoglobulins, and glycoproteins such as lactoferrin and mucins, which are produced by goblet cells in the mucous membranes and submucosal glands. Mucus serves to protect epithelial cells in the linings of the respiratory, digestive, and urogenital systems, and structures in the visual and auditory systems from pathogenic fungi, bacteria and viruses. Most of the mucus in the body is produced in the gastrointestinal tract.

<span class="mw-page-title-main">Mucin</span> Glycoprotein

Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell signalling to forming chemical barriers. They often take an inhibitory role. Some mucins are associated with controlling mineralization, including nacre formation in mollusks, calcification in echinoderms and bone formation in vertebrates. They bind to pathogens as part of the immune system. Overexpression of the mucin proteins, especially MUC1, is associated with many types of cancer.

Club cells, also known as bronchiolar exocrine cells, are low columnar/cuboidal cells with short microvilli, found in the small airways (bronchioles) of the lungs. They were formerly known as Clara cells.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">Simple columnar epithelium</span> Tissue type

Simple columnar epithelium is a single layer of columnar epithelial cells which are tall and slender with oval-shaped nuclei located in the basal region, attached to the basement membrane. In humans, simple columnar epithelium lines most organs of the digestive tract including the stomach, and intestines. Simple columnar epithelium also lines the uterus.

<span class="mw-page-title-main">Intestinal gland</span> Gland between the intestinal villi that produces new cells

In histology, an intestinal gland is a gland found in between villi in the intestinal epithelium lining of the small intestine and large intestine. The glands and intestinal villi are covered by epithelium, which contains multiple types of cells: enterocytes, goblet cells, enteroendocrine cells, cup cells, tuft cells, and at the base of the gland, Paneth cells and stem cells.

<span class="mw-page-title-main">Respiratory epithelium</span> Mucosa that serves to moisten and protect the airways

Respiratory epithelium, or airway epithelium, is a type of ciliated columnar epithelium found lining most of the respiratory tract as respiratory mucosa, where it serves to moisten and protect the airways. It is not present in the vocal cords of the larynx, or the oropharynx and laryngopharynx, where instead the epithelium is stratified squamous. It also functions as a barrier to potential pathogens and foreign particles, preventing infection and tissue injury by the secretion of mucus and the action of mucociliary clearance.

<span class="mw-page-title-main">Cysteinyl leukotriene receptor 1</span> Protein-coding gene in humans

Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT). CYSLTR1, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans as well as models of the reactions in other animals.

<span class="mw-page-title-main">Trefoil factor 3</span> Protein-coding gene in the species Homo sapiens

Trefoil factor 3 is a protein that in humans is encoded by the TFF3 gene.

<span class="mw-page-title-main">ZG16</span>

Zymogen Granule Protein 16 is a protein that is encoded by the ZG16 gene. Other common names include hZG16, FLJ43571, FLJ92276, secretory lectin ZG16, jacalin-like lectin domain containing, JCLN, JCLN1, MGC183567, MGC34820, ZG16A, zymogen granule membrane protein 16, zymogen granule protein 16 homolog, and zymogen granule protein. The gene is located on Chromosome 16: 29,778,256-29,782,973. The gene obtains one transcript and 128 orthologues.

<span class="mw-page-title-main">Mucociliary clearance</span>

Mucociliary clearance (MCC), mucociliary transport, or the mucociliary escalator describes the self-clearing mechanism of the airways in the respiratory system. It is one of the two protective processes for the lungs in removing inhaled particles including pathogens before they can reach the delicate tissue of the lungs. The other clearance mechanism is provided by the cough reflex. Mucociliary clearance has a major role in pulmonary hygiene.

<span class="mw-page-title-main">Foveolar cell</span> Mucus-producing cells in stomach lining protective against gastric acid

Foveolar cells or surface mucouscells are mucus-producing cells which cover the inside of the stomach, protecting it from the corrosive nature of gastric acid. These cells line the gastric mucosa. The mucus-secreting cells of the stomach can be distinguished histologically from the intestinal goblet cells, another type of mucus-secreting cell.

A chloride channel blocker is a type of drug which inhibits the transmission of ions (Cl−) through chloride channels.

<span class="mw-page-title-main">Intestinal mucosal barrier</span>

The intestinal mucosal barrier, also referred to as intestinal barrier, refers to the property of the intestinal mucosa that ensures adequate containment of undesirable luminal contents within the intestine while preserving the ability to absorb nutrients. The separation it provides between the body and the gut prevents the uncontrolled translocation of luminal contents into the body proper. Its role in protecting the mucosal tissues and circulatory system from exposure to pro-inflammatory molecules, such as microorganisms, toxins, and antigens is vital for the maintenance of health and well-being. Intestinal mucosal barrier dysfunction has been implicated in numerous health conditions such as: food allergies, microbial infections, irritable bowel syndrome, inflammatory bowel disease, celiac disease, metabolic syndrome, non-alcoholic fatty liver disease, diabetes, and septic shock.

Airway basal cells are found deep in the respiratory epithelium, attached to, and lining the basement membrane.

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

References

  1. 1 2 3 Hodges, R.R.; Dartt, D.A. (2010). "Conjunctival Goblet Cells". Encyclopedia of the Eye. pp. 369–376. doi:10.1016/b978-0-12-374203-2.00053-1. ISBN   9780123742032.
  2. ↑ Lohmann-Matthes, M-L.; Steinmüller, C.; Franke-Ullmann, G. (1994). "Pulmonary macrophages". European Respiratory Journal. 7 (9): 1678–1689. doi: 10.1183/09031936.94.07091678 . PMID   7995399.
  3. ↑ Saladin, K (2012). Anatomy & physiology : the unity of form and function (6th ed.). McGraw-Hill. pp. 88–89. ISBN   9780073378251.
  4. ↑ Ohar, JA; Donohue, JF; Spangenthal, S (23 October 2019). "The Role of Guaifenesin in the Management of Chronic Mucus Hypersecretion Associated with Stable Chronic Bronchitis: A Comprehensive Review". Chronic Obstructive Pulmonary Diseases. 6 (4): 341–349. doi: 10.15326/jcopdf.6.4.2019.0139 . PMC   7006698 . PMID   31647856.
  5. ↑ Evans, CM; Kim, K; Tuvim, MJ; Dickey, BF (January 2009). "Mucus hypersecretion in asthma: causes and effects". Current Opinion in Pulmonary Medicine. 15 (1): 4–11. doi:10.1097/MCP.0b013e32831da8d3. PMC   2709596 . PMID   19077699.
  6. ↑ "goblet cell" at Dorland's Medical Dictionary
  7. ↑ Guzman-Aranguez, A; Argüeso, P (2010). "Structure and biological roles of mucin-type O-glycans at the ocular surface". The Ocular Surface. 8 (1): 8–17. doi:10.1016/S1542-0124(12)70213-6. PMC   2847370 . PMID   20105403.
  8. ↑ Ross M, Pawlina W (2011). Histology: A Text and Atlas (6th ed.). Lippincott Williams & Wilkins. pp. 592–593. ISBN   978-0-7817-7200-6.
  9. ↑ Young B, Woodford P, O'Dowd G (2013). Wheater's Functional Histology: A Text and Colour Atlas (6th ed.). Elsevier. p. 94. ISBN   978-0702047473.
  10. 1 2 Johansson ME, Sjövall H, Hansson GC (2013). "The gastrointestinal mucus system in health and disease". Nature Reviews. Gastroenterology & Hepatology. 10 (6): 352–361. doi:10.1038/nrgastro.2013.35. PMC   3758667 . PMID   23478383.
  11. ↑ Johansson ME, Hansson GC (2013). "Mucus and the Goblet Cell". Digestive Diseases. 31 (3–4): 305–309. doi:10.1159/000354683. PMC   4282926 . PMID   24246979.
  12. 1 2 Rubin BK (2013). "Secretion properties, clearance, and therapy in airway disease". Translational Respiratory Medicine. 2 (6): 6. doi: 10.1186/2213-0802-2-6 . PMC   4215824 . PMID   25505698.
  13. 1 2 3 4 5 6 Adler, Kenneth Bruce; Tuvim, Michael J.; Dickey, Burton F. (2013). "Regulated Mucin Secretion from Airway Epithelial Cells". Frontiers in Endocrinology. 4: 129. doi: 10.3389/fendo.2013.00129 . ISSN   1664-2392. PMC   3776272 . PMID   24065956.
  14. ↑ Birchenough, G. M. H.; Johansson, M. Ev; Gustafsson, J. K.; Bergström, J. H.; Hansson, G. C. (July 2015). "New developments in goblet cell mucus secretion and function". Mucosal Immunology. 8 (4): 712–719. doi:10.1038/mi.2015.32. ISSN   1933-0219. PMC   4631840 . PMID   25872481.
  15. ↑ Histology image:11303loa from Vaughan, Deborah (2002). A Learning System in Histology: CD-ROM and Guide. Oxford University Press. ISBN   978-0195151732. - Digestive System: Alimentary Canal: fundic stomach, gastric glands, lumen"
  16. 1 2 McDole; et al. (2012). "Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine". Nature. 483 (7389): 345–349. Bibcode:2012Natur.483..345M. doi:10.1038/nature10863. PMC   3313460 . PMID   22422267.
  17. 1 2 Lambrecht, Bart N; Hammad, Hamida (2015). "The immunology of asthma". Nature Immunology. 16 (1): 45–56. doi:10.1038/ni.3049. PMID   25521684. S2CID   5451867.
  18. 1 2 3 4 Kuperman, Douglas A.; Schleimer, Robert P. (August 2008). "lnterleukin-4, lnterleukin-13, Signal Transducer and Activator of Transcription factor 6, and Allergic Asthma". Current Molecular Medicine. 8 (5): 384–392. doi:10.2174/156652408785161032. ISSN   1566-5240. PMC   4437630 . PMID   18691065.
  19. 1 2 3 4 Zhao, Jinming; O'Donnell, Valerie B.; Balzar, Silvana; St. Croix, Claudette M.; Trudeau, John B.; Wenzel, Sally E. (2011-08-23). "15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells". Proceedings of the National Academy of Sciences of the United States of America. 108 (34): 14246–14251. Bibcode:2011PNAS..10814246Z. doi: 10.1073/pnas.1018075108 . ISSN   0027-8424. PMC   3161579 . PMID   21831839.
  20. 1 2 Holt, N; Grønbæk, H (2013). "Goblet cell carcinoids of the appendix". The Scientific World Journal. 2013: 543696. doi: 10.1155/2013/543696 . PMC   3556879 . PMID   23365545.
  21. ↑ McCusker, ME; Coté, TR; Clegg, LX; Sobin, LH (2002). "Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998". Cancer. 94 (12): 3307–12. doi: 10.1002/cncr.10589 . PMID   12115365. S2CID   40814989.
  22. ↑ Fouad, YM; Mostafa, I; Yehia, R; El-Khayat, H (2014). "Biomarkers of Barrett's esophagus". World Journal of Gastrointestinal Pathophysiology. 5 (4): 450–456. doi: 10.4291/wjgp.v5.i4.450 . PMC   4231509 . PMID   25400988.
  23. 1 2 3 4 5 Vatrella, Alessandro; Fabozzi, Immacolata; Calabrese, Cecilia; Maselli, Rosario; Pelaia, Girolamo (2014-09-04). "Dupilumab: a novel treatment for asthma". Journal of Asthma and Allergy. 7: 123–130. doi: 10.2147/JAA.S52387 . ISSN   1178-6965. PMC   4159398 . PMID   25214796.
  24. ↑ Felts, William J. L.; Harrison, Richard J. (2015-08-26). International Review of General and Experimental Zoology. Elsevier. p. 244. ISBN   9781483224824.
  25. 1 2 "Chapter IV:The Goblet Cell in General". Acta Ophthalmologica. 46 (S95): 25–35. 1968-02-01. doi:10.1111/j.1755-3768.1968.tb05926.x. ISSN   1755-3768. S2CID   221392598.
  26. ↑ Vázquez-Sánchez, María Ángeles. "CacoGoblet". Readycell. Retrieved 20 July 2018.
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