2015 Group 3 Project

From CellBiology
Revision as of 11:16, 30 May 2015 by Z3463637 (talk | contribs)

Extracellular Matrix 2015 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

Projects are now locked for final Assessment.

Elastic Fibres


Elastic fibres are abundant within the extracellular matrix of connective tissues such as the skin, blood vessels, lungs and ligaments. [1] It provides resilience and the mechanical recoil of tissues and organs to repetitively deform and reform to its original shape without compromising structural integrity. This deformability is essential to the functioning of tissues. Its recoiling properties are attributed to the elastin polymer that makes up most of the elastic fibre. [2] The impairment or loss of elastic tissues results in profound pathological implications.


Elastin was first recognized in the mid 19th century, but due to its high insolubility, it was an extremely difficult protein to study. Substantial progress in the study of elastin was hindered until the soluble precursor, tropoelastin, was discovered in the early 1970s. This sparked significant interest in the study of elastin and elastic fibres. In the late 1970s, Helene Sage and William Gray used histological staining techniques and amino acid composition to identify elastin in arteries of vertebrates and non-vertebrates. The Gordon Research Conference on elastin began in 1976, which represented a large international interest group in this area. Due to its success, it has been held every year since, with scientists revealing their studies of the biochemistry, pathology, cellular and molecular biology of the protein elastin.

Graphical representation of the number of published papers related to Elastic Fibres in the PubMed database which indicates the progress of research.

By 1995, the conference name changed from “Elastin” to “Elastin and Elastic Fibers” which highlights the progress of research, which has extended from the single elastin protein to the entire Elastic Fibre Matrix. This encompassed the discovery of microfibrils and microfibrillar associated proteins as scientists continued to describe the Elastic Fibre structure. With the years to follow, this field has continued to expand to discover many other molescules that influence the function, regulation and assembly of Elastin fibres that include lysyl oxidases, fibulins, emilins and proteoglycans.

Structure and Components

Cross section of arteries with elastin (Left) and with elastin removed (Right)

Elastic fibres play a significant role in the extracellular matrix of cells and the organisation of elastic fibres varies in different tissues. In the lungs, skin and ligaments, elastic fibres are organised in a rope-like manner, in blood vessels it is organised as thin concentric sheets and has a large honeycomb structure in elastic cartilage. Elastic fibres are composed of two significant components; 90% of which is an amorphous core of highly cross-linked elastin protein and the remaining 10% is a fibrillar mantle of microfibrils. [1]

Tropoelastin and Elastin

Elastin is a very insoluble complex structure, being one of the most insoluble proteins of the human body. [3][1] The study of Elastin was significantly hindered due to its insolubility. With the discovery of the soluble precursor of elastin, tropoelastin, scientists were able to describe chemical properties of elastin. [4]

Tropoelastin and elastin are made significantly of only four hydrophobic amino acids: glycine, alanine, valine and proline. Mature elastin appears as an amorphous branching structure with extensive cross-linking tropoelastin monomers. An important feature of the composition of pure elastin is the absence of methionine, histidine and tryptophan. [1] Desmosines and its isomer, isodesmosine are formed from the covalent cross-linking of four lysine residues that are unique to elastic fibres and are responsible for the its hydrophobic properties. [3] Lysyl oxidase (LOX) is the enzyme that initiates cross-linking within elastin as it modifies lysine residues to form desmosines and isodesmosine. [5]

Under a light microscope, elastin is typically recognised by its wavy appearance. [1]


During the assembly of elastic fibres, microfibrils function as a scaffold for the deposition of elastin. [6] The microfibrillar region is organised with 10-12nm fibrils with a beaded appearance that are loosely parked into parallel bundles to form a sheath around the amorphous elastin core. [1] The major structural component of the microfibrils is fibrillins, large rod-like cystine-rich glycoproteins. Three fibrillins have been identified: Fibrillin-1, Fibrillin-2 and Fibrillin-3. Fibrillin-1 has Arg-Gly-Asp sequences that interact with integrins located on the cell surface and is believed to have a role in signalling during elastic fibre assembly. Fibrillin-1 and -2 are responsible for mediating the binding of tropoelastin to the microfibril. It is currently unknown whether Fibrillin-3 is related to elastic fibres. [5]

Microfibrillar Associated Proteins

The outer mantle of fibulin-rich microfibrils has many distinct proteins associated with it. Microfibril associated glycoproteins-1 (MAGP-1) and MAGP-2 and are small glycoproteins proteins that are important for structural integrity of elastic fibres. [3] MAGP-1 is able to bind with fibrillin-1,tropoelastin and is believed to be involved in elastic fibre assembly as it bridges the two molecules together. [7] MAGP-2 interacts with and binds to fibrillin-1 and fibrillin-2 and is believed to be functionally involved in cell signalling in the assembly of microfibrils.

Fibulins are a family of five different acidic glycoproteins, but fubulin-1, fibulin-2 and fibulin-5 are the three that are most implicated in the biology of elastic fibres. Fibulin-1 is not associated with individual microfibrils but is associated with the elastin core of elastic fibres. Fibulin-5 localises to the interface of elastin and microfibrils. Fibulin-2 is able to strongly bind with tropoelastin and fibrillin-1. Fibrilin-4 has some but relatively weaker affinity to tropoelastin. [8]

Elastin microfibril Interface Located Protein (EMILIN)-1 is another microfibril protein localises to the elastin-microfibril interface. EMILIN-1 is able to regulate the deposition of tropoelastin on microfibrils and bind elastic fibres to the surface of cells. [9]

Assembly of Elastic Fibre

Process of Elastic Fibre Assembly
Role of MFAP-4 in Elastic fiber assembly

The formation of Elastic fibers is a complex process which is comprised of multiple interactions between different proteins, enyzmes and binding sites. Elastic fibers are mostly comprised of Elastin and Micro-fibrils which consist make up most of the structure, the processes of formation are closely regulated and carried out by the smaller protein components; Tropoelastin, Lysyl Oxidases (LOX), Fibrilin-4 / Fibrilin-5 and Integrins

Initially, Tropoelastin molecules are secreted from elastogenic cells [10] (e.g. dermal fibroblast, vascular smooth muscle cells and lung alveolar cells) as a soluble precursor [11] that has a mass of approximately 70 kDa [12]. These Tropoelastin molecules undergo the process of coacervation [13] where the molecules rapidly self-associate, driven by the hydrophobic interactions to form protein rich aggregates. These aggregates of Tropoelastin are organized in a cross-linked manner and guided by a 67-kDa elastin-binding protein to the cell surface [14] with the assistance of glycosaminoglycans as well as one or more proteins from the Lysyl Oxidase family [15].

Within the aggregates Tropoelastin molecules, Fibulin-4 and/ or Fibulin-5 ECMP (extracellular matrix proteins), work to facilitate and assist in the cross-linking of the individual Tropoelastin molecules as well as to maintain and limit the size of the forming aggregates [16] on the cell surface . Fibulin-4 and Fibulin-5 ECMP’s are crucial molecules in the assembly of elastic fibres and also play a non-redundant role during elastic fibre formations [17]. Newly generated Tropoelastin molecules from elastogens continuously attach to growing pre-existing aggregates or proceed to form their own aggregates with the assistance of LOX.

Coacervated tropoelastin molecules from the cell surface are then deposited to the onto micro-fibrils, which acts as a scaffold allowing for the formation of elastic fibres, held near the cell surface by integrins. Integrins are the trans-membrane receptors which are the bridges for cell-cell interactions [18]. Upon transportation and attachment to the micro-fibril structures, coalesced Tropoelastin molecules form larger aggregates on the whole surface of the fibres with the assistance and regulation of more LOX and Fibulin proteins leading to the complete formation of elastic fibres when enough aggregates have been attached.

1. Initially Tropoelastin is secreted by cells and then organized into cross-linked aggregates on the cell surface with the assistance with cell surface glycosaminoglycan’s and one or more LOX

2. Fibulin-4 and/or Fibulin-5 closely interacts with the aggregated Tropoelastin molecules on the cell surface to facilitate the cross-linking or to limit the aggregate size

3. Newly generated Tropoelastin molecules are constantly formed and attaches to elastin aggregates already exist on the cell surface. These larger aggregates are then transferred onto pre-existing Microfibrils

[Microfibrils are made primarily of Fibrilin-1 and/or Fibrilin-2, possibly containing other microfibril associated proteins. These Microfibrils bind to the cell surface via Integrins which are transmembrane receptors which bridge cell-cell interactions]

4. Fibulin-4 and Fibulin-5 both bind to Fibrilin-1 and may help transfer the elastin aggregates to the microfibril

5. Elastin aggregates on the microfibril coalesce into larger structures and are further cross-linked by LOX and/or LOXL to form the complete and functional elastic fibre, during this stage, Fibulin-4 and/or Fibulin-5 may assist in facilitating cross-linking


Structure serves as function

If you think about a rubber band, it can be stretched when a force is applied to it. When the force stretching the rubber band is released, the rubber band resumes back to its original shape. Similarly, with age and repetitive stretching of the skin the elastic fibres that produce this elongation become less "elastic" resulting in reduced resilience, recoiling and adaptability.

Often the structure inside a biological system will serve well its main function. This can be clearly seen in cross sections of the branches of the aorta, stemming from the heart. What can be seen in histological cross sections are walls that are thick, muscular and contain high amounts of elastic fibres. The reason for this is that blood exiting the heart via the aorta needs to supply all the organs of the human body. Therefore, understandably, it is under enormous pressure and carries large volumes of blood. The structure of the artery needs to be able to carry out function. The histological diagram below shows the different components, that allow this important function to take place. The main component, however that will be focused upon is the elastic fibres contained within the tunica intima and tunica adventitia known as the internal and external elastic lamina respectively.

Tropoelastin - a versatile, bioactive assembly module [19]

The monomer for elastin is tropoelastin. Thus when many Tropoelastin molecules are bonded together (covalent bonds )with cross links such as lysal oxidase [20] they bind together to form the protein elastin. There is only one gene for that codes for tropoelastin and thus only one protein. The research stems on the facts that tropoelastin is compatible with synthetic and natural co-polymers. As a result of this, it enables these researches to expand upon the applications of its potential use in next-generation tailored bioactive materials such as when responding to injury. This is because large quantities of the monomer have only become accessible recently. Isolation of tropoelastin was previously intricate and inefficient due to its rate of cross linking incorporated into growing the elastic fiber in the living. However by synthesizing the elastin gene, this has allowed for a recombinant tropoelastin that is identical to the naturally secreted human form giving that compatibility that allows scientist and research to work with in a versatile way.


Changes in the structure-function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves [21]

Elastin is commonly found in the arteries due to the high pressure of blood coming from the heart, and its function to supply oxygenated blood to all organs, its elasticity is important due to enormous pressure it needs to withstand. Pulmonary arterial hypertension (PAH) causes stiffness in these arteries affecting the ability for these arteries to stretch and maintain a relatively constant pressure with high blood flow. This article looks at the structure and function of this relationship in PAH and the mechanobiological adaptations that are undergone by elastic arteries in response to PAH.

Spatial Distribution and Mechanical Function of Elastin in Resistance Arteries A Role in Bearing Longitudinal Stress [22]

Arteries within the human consists of three layers and are most evident closest to the heart due to the properties that make them withhold the enormous pressure the heart pumps. The walls of the arteries exist in three layers where the outermost layer, called the tunica adventitia providing tensile strength, the hypothesis this research grouped investigated was whether the elastin fibres are subject to longitudinal stretch.

Elastic Artery Histology.jpg Damaged Elastic Lamina in Blood Vessel.png


Elastic fibres are ubiquitous in the lung, for the need to expand and stretch with every breath that is inhaled and recoil back to its original resting state with air is exhaled. Elastic fibres are mainly found in the terminal branches of the respiratory tree, their ubiquity is increased, and the structure of the fibres take on a circular or helical arrangement as you move down the respiratory tree. In order for maximum contact to occur between the terminal branches of the respiratory tree, the alveoli, and the oxygen breathed in, a cyclic (expansion and shortening) exchange surface area is provided for by elastic fibres. Research has suggested that elastin and collagen fibres from alveoli, bronchi, interlobular septae, and the pleura all appear to have associations with the fibres of the pulmonary arteries.

As with the heart, elastic fibres in the lung are arranged in circular and longitudinal arrangements. [23]

Elastin Respiratory Histology.jpg


The importance of elastic fibres in skin is noticeably evident in the older age of men and woman. Thereby through through the aging process elastic fires become stiff and less resilient to stress. Recent research has focused on the generation of collagen elastin in three dimesnional imaging of the human dermis to further understand the micro-structures of the skin, which is believed to be helpful in the fabrication of bionic engineered skin. [24]



Skin is composed of five layers.

Comparison between human fetal and adult skin [26]

Elastin is important in adults for restoring backing the normal tissue architecture example pinching of skin. According to this research, extracellular components such as elastin are important in the scarless healing process that takes places in on early fetal gestation. The role that elastin or another name, tropoelastin is investigated. Elastin is not found in fetal skin up till week 22. Although it is not a primary extracellular component for scarless healing in fetal wounds, it is still plays a role in skin regeneration. A comparison between fetal skin and adult skin is looked at.

Insights into the role of elastin in vocal fold health and disease [27]

Elastin can be defined as a an extracellular matrix protein that is responsible for tissue elastic recoil. Therefore, because of its function it can then be assumed that it is found in different parts of the human body that require tissue recoiling. For example, lungs(30%)- expansion when inhaling and exhaling air, large arteries (70%)-to be able to recoil back to their shape consistently as blood is bumped through them, skin (2-4%)- to be able to withstand stretches and sustain its original shape. Elastin can also be found in the vocal fold of the lamina propria, making up 9% of the total protein. Thus, the lamina propria experiences greater amounts of mechanical strain relative to skin but less when compared to lungs and arteries.

Clinical Significance

Ebola Virus [28]

Ebola virus is an aggressive pathogen that causes a highly lethal hemorrhagic fever syndrome in humans with mortality rates varying between 50 to 90%. An important manifestation of Ebola virus infection is Disseminated Intravascular Coagulation, which is a syndrome characterized by systemic intravascular activation of coagulation and generalized deposition of fibrin in the circulation. As clinical manifestations, the Ebola virus disease can be composed by hypotension, generalized fluid distribution balance, lymphopenia, coagulopathy, hemorrhage and high fever.

Based on previous studies, it was suggested that the Ebola virus glycoprotein is the main determinant of vascular cell injury and thus it was proposed that the direct Ebola virus replication-induced structural damage of endothelial cells triggers the hemorrhagic diathesis. This study suggested, by using the ISM technique (information spectrum method), that the EMILINs (Elastin Microfibril Interface Located Proteins), which are expressed mostly in the vasculature extracellular matrix and distributed throughout the blood vessel walls, play a relevant role in interaction between Ebola virus glycoprotein and the endothelial extracellular matrix, contributing to the infection and the pathogenesis of Ebola virus by damage of the extracellular matrix and vascular homeostasis. While EMILINs are well known to play a role in coagulation, as a component of the vessel wall and a component of the thrombus, these proteins could also be involved in Disseminated Intravascular Coagulation by interaction with Ebola virus glycoprotein.

Pulmonary emphysema [29]

The lung is a very complex and sophisticated matrix structure on which lung epithelium and endothelium reside. The typical destructive lung disease is pulmonary emphysema, a destructive process encountered mostly in smokers and a disease component of chronic obstructive pulmonary disease (COPD). COPD is characterized by persistent airflow limitation that is usually progressive and related to an enhanced chronic inflammation response in the airways and the lungs to noxious particles or gases. Inhaled cigarette smoke and other noxious particles such as smoke from biomass fuels cause lung inflammation, a normal response that appears to be modified in patients who develop COPD. This chronic inflammatory response may induce parenchymal tissue destruction, resulting in emphysema, and disrupt normal repair and defense mechanisms, resulting in small airway fibrosis. These pathological changes lead to air trapping and progressive airflow limitation, causing breathlessness and other characteristic symptoms of COPD. [30]

The study aimed to understand the roles matrix metalloproteinases play in the development of pulmonary emphysema. Matrix metalloproteinases contribute substantially to lung matrix degradation during the evolution of cigarette smoke induced emphysema by destruction of both elastin and collagen matrix proteins. Elastin and collagen are very important proteins for the maintenance of the lung architecture and structure, and therefore degradation of both elastin and collagen is required for the development of pulmonary emphysema, though evidence remains strongest for elastin, since adults are effectively incapable of elastic fiber repair.

Thrombosis [31]

The clinical manifestations of arterial and venous thrombosis represent the leading causes of death in the developed world. While arterial and venous thrombosis have important pathobiological differences, both are complex and influenced by multiple genetic and environmental factors. Acute thrombosis at the site of a plaque is thought to be a precipitating event in the transition from a stable or subclinical atherosclerotic disease to acute myocardial infarction, ischemic stroke or peripheral arterial occlusion, all important conditions that might lead the patient to death. For individuals undergoing surgery, pulmonary thromboembolism and venous thrombosis are common. [32]

The EMILIN proteins are a family of extracellular matrix glycoproteins that play important role not only in elastogenesis and vascular architecture, but also in hemostasis and thrombosis. EMILIN2, Elastin Microfibril Interface Protein2, was identified as a gene expressed during cardiovascular development, on cardiac stem cells, and in heart tissue in animal models of heart disease. In humans, EMILIN2 gene is located on the short arm of chromosome 18, and patients with partial and complete deletion of this chromosome region have cardiac malformations. The results presented by the study indicated that EMILIN2 is necessary for platelet aggregation, clot retraction and thrombus formation, showing that it has multiple influences in pathophysiology of thrombosis and suggested that its role as a prothrombotic risk factor may arise from its effects on platelet aggregation.

Vitamin A deficiency and alterations in the extracellular matrix [33]

Vitamin A or retinol can be considered the most multifunctional vitamin in mammals. It has a lot of biological roles and it is known to modulate the synthesis of extracellular matrix proteins, including elastin. For this reason, the structure and composition of this extracellular compartment is deeply altered as a result of vitamin A deficiency. Its deficiency, along with protein malnutrition, is currently the most common and serious nutritional disorder worldwide. Biologically, vitamin A is important for normal embryonic development and organogenesis, and exert major effects on postnatal tissue homeostasis, vision, reproduction, immune function, growth, cellular differentiation, proliferation and apoptosis. In agreement with the multiple functions of retinoids, deficiency of vitamin A leads to a spectrum of clinical manifestations, known as vitamin A deficiency disorders. These include mild to severe xerophtalmia, squamous metaplasia of transitional and glandular epithelia, growth disturbances, anemia, susceptibility to infections and increased mortality.

The study aimed to show that altered extracellular matrix will potentially compromise organ function and lead to diseases, like liver, pulmonary and renal fibrosis, which are common pathological states associated with alterations in the extracellular matrix, giving to vitamin A a very important role in the maintenance of an adequate extracellular matrix and thus organ function.

Future Directions

Elastic Fibres are very large and complex structures, and are still quite poorly understood component of the extracellular matrix. Challenges for the future include describing how cells are able to regulate microfibril and elastic fibre assembly, by establishing the hierarcy of molecular interactions and the molecular composition. Research continues to better describe the biomechanical properties of microfibrils and microfibril associated proteins. At the organism or phenotypic level, there is very little understanding about how elastic fibres influence the behavious of cells. A priority of future research includes aiming to identify cellular receptors, signalling mechanisms and growth factors. With continued progress in the area, we will be able to grasp a greater understanding of Elastic fibres that will assist in the developing methods for elastic fibre regeneration or repair to manage the effects of ageing and diseases.


  1. 1.0 1.1 1.2 1.3 1.4 1.5 <pubmed>9851686</pubmed>
  2. <pubmed>8761465</pubmed>
  3. 3.0 3.1 3.2 <pubmed>12082143</pubmed>
  4. <pubmed> PMC3060269</pubmed>
  5. 5.0 5.1 <pubmed>18228265</pubmed>
  6. <pubmed>11426877</pubmed>
  7. <pubmed>10793130</pubmed>
  8. <pubmed>8702639</pubmed>
  9. <pubmed>10358019</pubmed>
  10. <pubmed>1603038</pubmed>
  11. <pubmed>1208143</pubmed>
  12. <pubmed>18468477</pubmed>
  13. <pubmed>21081222</pubmed>
  14. <pubmed>2546580</pubmed>
  15. <pubmed>11642359</pubmed>
  16. <pubmed>18228265</pubmed>
  17. <pubmed>24613575</pubmed>
  18. <pubmed>12297042</pubmed>
  19. <pubmed>PMC3879170</pubmed>
  20. <pubmed>PMC3190022</pubmed>
  21. <pubmed>PMC2593497</pubmed>
  22. <pubmed>PMC3380608</pubmed>
  23. <pubmed>PMC24748954</pubmed>
  24. <pubmed>PMC25781868</pubmed>
  25. <pubmed>PMC15036271</pubmed>
  26. <pubmed>PMC2799629</pubmed>
  27. <pubmed>PMC3190022</pubmed>
  28. <pubmed>PMC4333865</pubmed>
  29. McGarry Houghton A., Matrix metalloproteinases in destructive lung disease, Matrix Biol (2015),http://ac.els-cdn.com/S0945053X15000396/1-s2.0-S0945053X15000396-main.pdf?_tid=1c4289b8-f84e-11e4-9668-00000aab0f01&acdnat=1431397689_b69dfdf01822da057f0ca980cde0b08e
  30. 2015 Global Initiative for Chronic Obstructive Lung Disease, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015.pdf
  31. <pubmed>PMC4319747</pubmed>
  32. <pubmed>PMC3113922</pubmed>
  33. <pubmed>PMC4245576</pubmed>