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Basement Membrane

Basement Membranes throughout the Body

Introduction

The Basement Membrane (BM) is a thin layer of specialized extracellular matrix(ECM) which serves as a support structure for which epithelium grows upon, as well as, surrounds muscle cells, fat cells, and neural(Schwann) cells. It also provides mechanical support, compartmentalizes tissues, and influences cellular behaviour [1]. Some of the major molecular structures involved in the BM are Collagen IV, laminin, proteoglycans[2], and nidogen/enactin. Minor structures of the BM include agrin, SPARC/BM-40/osteopontin, fibulins, type XV collagen and type XVIII collagen. Currently, roughly 50 proteins that contribute to the BM structure have been identified[3]. This page focuses on the structure, function, and formation of the BM, in addition to exploring historical and current research, as well as, abnormalities.

History

The basement membrane was first described by Bowman in 1840 as a membranaceous sheath of the most exquisite delicacy in muscle. It wasn't until the 1970's that laminin, type IV collagen, nidogen and perlecan were identified. [4].

Date Event
1840 Bowman, Membranaceous sheath of most exquisite delicacy
1957 Todd and Bowmen first describe the basement membrane and suggested that they were continous sheets around tissues
1950-60s Electron microscopes are used in the study of BM and it's revealed them to be separate structures to the ECM
1970 Laminin, type IV collagen, nidogen and perlecan
1972 BM formed scaffolding that nerve and muscle cells follow during regeneration
1983 Anchoring fibers of BM were identified - collagen type VII
1985 'Lamina lucida' 'lamina densa' and 'lamina fibroreticularis' become internationally recognised as terms referring to BM structure
1900 Lindemann mouse model of nephritis evoked intrest in [5]
Formation of Basement Membrane

Formation, Plasticity and Regeneration

The large, insoluble molecules that make up the BM form sheet-like structures through the process of 'self-assembly'. This congregation of cells is mediated by cell-surface anchors and receptors. Elements such as laminin and collagen IV are supplied from other cells within the body to form some components of the BM. Information within the primary sequences of laminin and type IV collagen initiates intermolecular self-assembly. Other minor components, such as perlecan and nidogen/entactin, do not have the capability to instruct this assembly. However, these minor components facilitate the interaction of independent type IV collagen and laminin scaffolds.

Laminin provides the center framework inside the cell, with type IV collagen providing the attached scaffold, giving strength to the cell and surrounding BM cells. Laminin polymers are deposited via site-specific interactions by cell-surface proteins such as Beta1 integrins and dystroglycans. Type IV collagen polymers bind with laminin polymers on the cell surface via nidogen/entactin bridging. These interactions create the fully functional BM.[3]

BM specialization occurs through tissue-specific isoformes of laminin and collagen IV, as well as, particular proteoglycan populations.[6] BM thickness can range between 50-100nm depending on the localization in the body and the ratios of different isoformes of molecular components.[3]

The basement membrane is not a static structure. It is constantly regenerated creating different ratios of ECM proteins over the life of an organism.[7] Therefore, although most BMs are within this range, they can be less than 50nm or more than 100nm depending on how they are organized at any particular point.

Functional Layers

The BM has morphological differences between the epithelial, outward facing side, and stromal, inward facing side. It is hypothesized that the sidedness of the BM is due to the process of BM formation and the rates of synthesis of BM components. Laminin is the first to bind to cellular receptors on the epithelial cell surface followed by the attachment of collagen to this laminin template. This gives reason for the increased laminin detected in the basal lamina and increased collagen IV in the reticular lamina.

These layers are fused together by hemi-desmosomes, as seen in the photo below, and by dermal collagen connections. Hemi-desmosomes connect epithelial cells to the lamina lucida and lamina densa layers. From the stromal side, dermal collagen extends through the reticular lamina and into the lamina densa connecting the basement membrane to the connective tissue below.

File:Basement Membrane Layer Interactions.jpg
Basement Membrane Layer Interactions

Basal Lamina

Basal means base and lamina means thin layer. This thin, base layer lies underneath epithelial cells. It is also recognized as the apical layer of the BM. Due to exhibiting high levels of laminin proteins, Laminin 521 being the most common, this layer promotes epithelial cell adhesion. The basal lamina can be split into two layers, the lamina lucida and the lamina densa.

The lamina lucida was given its name by its' lucid, transparent appearance. This layer consists of laminin, integrins (for desmosome binding), entactins, and dystroglycans. The lamina densa was given its name due to its' dense appearance. This layer can range between 30 and 70nm thick[8] The lamina densa contains collagen IV fibres coated in perlecan. Perlecan is rich in heparan sulfate. This produces the molecular impermeability of the BM.[9]

Reticular Lamina

Coming from the word reticulum, meaning 'a fine network or net-like structure', the reticular lamina is a thin layer of network-forming collagen. This layer is the stromal side of the BM and faces connective tissues. The reticular lamina exhibits high levels of collagen IV, in particular, collagen IV α3/4/5. It's main purpose is to bind to connective tissue proteins, such as members of the fibrillar collagens. Unlike the basal lamina, it has an anti-adhesive quality for epithelial cells. This is thought to prevent the formation of directly apposed epithelial cell layers [10]

Structural Components

It has been found that the majority of the BM consists of water tightly joined by proteoglycans. Nevertheless, laminin and type IV collagen are the most abundant components of the BM. Basement membranes vary in thickness and strength due to the different combinations of these component's isoformes. Isoformes of laminin and type IV collagen share significant homologies; however, their amino-acid sequence may differ by 30-50%.[3] Research has yet to determine which isoformes of laminin and collagen IV are found in the different BMs within the body, as well as their abundance.

Laminin

Laminin is a large glycoprotein.[11] It is the most abundant noncollagenous protein in the BM[12] aiding in epithelial attachment to BM Type IV collagen.[13] Laminin has been determined to be the most important regulator of cellular functions and plasticity.[14]

Collagen IV

Collagen IV compromises 50% of all BM proteins. 6 different type IV collagen α-chains have been identified in association with the BM. These α-chains can have 56 possible combinations of trimers. Collagen XV and XVIII have also been discovered in small amounts within the BM.[3]

Heterogeneity of Basement Membrane

Basement membranes are highly diverse and tissue specific. Differences in the amount of basement membrane components, such as laminin, IV collagen, perlecan and nidogen, as well as the varied subtypes of these components, are usually what causes basement membrane heterogeneity [15].

For example, in kidney the α3α4α5 type IV collagen protomer is found in the glomerular basement membrane (GBM), whereas α5α5α6 (speculative) and α1α2α1 protomers are found in the Bowman’s capsule BM. Furthermore, in the kidneys there are at least 3 different types of collagen [16]. The diversity of these collagen and laminin subtypes found in the Kidney are essential for allowing tissue specific functioning. The composition of the BM of the tubular epithelium allows for osmoregulation whilst the BM in glomerular epithelium allows for plasma filtration. The BM proteins are also “encoded by differentially regulated genes” thus particular components of the BM can be down regulated or up regulated depending on the tissue [17].

Basement Membrane Functions

The basement membrane serves a wide array of functions depending on the type of tissue it is located in. In general, it serves as a cell supporting matrix, organizes the cell monolayers during tissue development, acts a tissue barrier, participates in cell adhesion and has ligands for cell surface receptors. Laminin and type IV collagen form the meshwork of most basement membranes while its' functions are maintained by cell surface receptors such as integrins and dystroglycans. [18][19]

Glomerular Basement Membrane

The image shows the normal nephron structure including a glomerular basement lining the glomerulus.

Kidney

In the kidneys, the BM acts a semi permeable selective barrier which allows for filtration of the wastes from the blood. Thus, the BM in kidneys varies from most other BMs found throughout the body. It mainly consists of α3α4α5 type IV collagen network, the laminin 10/11 polymer, and perlecans which provide mechanical strength.[20] This BM was also thought to have charge properties to allow for filtration of blood; however, this is not confirmed. [21][22]

Skin

In the skin, the BM is connected to the dermis via anchoring fibrils. The type VII collagen of these anchoring fibrils binds to laminin 332. [23]. Collagen I and II fibrils are also interwoven. This forms a strong adhesion complex necessary for protecting the structural and functional integrity of the skin [24]. A study found that knockout of Lama3 gene which expresses laminin-332 was lethal at neonatal stage and resulted in loss of cell adhesion. In other cases, defects of skin basement membrane of its associated molecules can result in skin blistering. [25]

Vasculature

Vascular basement membranes can act as a barrier to transmigration of leukocytes during inflammation. In neoplasia, cancer metastasis require that cancer cells cross the vascular and non-vascular basement membrane. However, the BM is a tight, cross-linked framework formed by laminin and type IV collagen polymers, bridged by nidogens. This makes it very difficult for cells to pass through it[26]. Studies suggest that microvascular basement membranes in pancreas blood vessels allow for insulin gene expression, as well as, promotion of B islet cell proliferation via laminin binding to β1 integrin. [27] Furthermore, binding of α4 laminin to the α6β1 integrin modulates T lymphocyte extravasation. This can allow laminin α4 to promote and laminin α5 to inhibit the T lymphocyte extravasation at postcapillary venules in the CNS. [28]

Basement Membrane in Neoplasia

Neoplasia

The BM also acts as a reservoir for growth factors. For example, in neoplasia, one of the growth factors vascular endothelial GF (VEGF) promotes angiogenesis at sites of injury[29]. XVIII collagen is cleaved and released from the basement membrane during remodeling and it is anti-angiogenic, thus, prevents tumor growth.[30]

Development

Nidogen 1 and nidogen 2 knock out mice have been used to demonstrate the importance of BM in optimal organ function. Functional redundancy of nidogen in these mice are “perinatally lethal” which highlights the importance of this glycoprotein allowing for BM formation in the lung and heart.[31] However, other organs develop as per normal suggesting that BMs of different organs have different compositional requirements for optimal tissue functioning.

Cell signalling

The mechanical, viscoelastic properties of ligand bearing polymers on BM allows them to transmit information to cells, and thus, play a part in cell signalling[32]. Basement membranes contain gel consistency polymers that can increase in viscosity as the concentration of laminin or type IV collagen is increased. The laminin-111 gels have been found to promote glandular differentiation and milk production in mammary glands through signaling.[33]

Smooth Muscle

In smooth muscle, there are linkages from the basement membrane to stromal collagen that contribute to sarcolemma stabilization [34]. Mutations affecting any of the key links (dystrophin, dystroglycan-binding to basement membrane, laminin-211, and type VI collagen) result in a muscular dystrophy.[35]

Related Video

This video provides an overview of the content we have covered so far. The media player is loading... [36]

Abnormalities

In this portion of the page, we will discuss abnormalities that may occur in the development of the basement membrane. The content will cover several common basement membrane diseases, as well as some rare forms of abnormalities related to the formation of the basement membrane. This will incorporate genetic predispositions, including some that may lead to cancer progression. There are currently numerous methods used to ensure patients are able to treat the diseases early on and to even detect them among children prior to their birth. This is conducted through genetic testing to ensure best treatment is established at an early diagnosis.

The most common abnormalities of the basement membrane involve the renal system of the body. When normal homeostatic functioning is perturbed due to diseases in the basement membrane of the glomerulus, then filtration of the blood will no longer be sufficient. These diseases will be covered first, as there are many, and some more common than others. We will also cover several other diseases associated with the basement membrane. Diabetes and hypertension also cause many complications and even cancers that are best distinguished to be malignant as a result of invasion through the basement membrane.


Additional info Glomerulus
Glomerulus
Glomerulus structure

The glomerulus is a component of the kidney nephrons. Its role is to filter the blood and form waste products (urine). The glomerulus consists of a network of capillaries which increases the surface area. It is surrounded by the Bowman's capsule. Together these two components form the Renal corpuscle [37]. The glomerulus is composed of the glomerular basement membrane (GBM) which lies between podocytes and endothelial cells. The GBM is made up of type IV collagen, nidogen, heparan sulfate proteoglycan and laminin [38]. Mutations associated with any of these components will cause defects in renal filtration. Diseases associated with the Glomerulus will form scarring or swelling which damages the lining. This can interfere with filtration of waste products from the kidney. Thus, a build up of waste products may occur resulting in more life threatening conditions. [39]

Normal Glomeruli showing the Glomerular Basement Membrane

[40]

Renal Abnormalities

Retinopathy in X-linked Alport Syndrome

Alport syndrome

Alport syndrome is charcaterised genetically and clinically as a heterogenous nephropathy. There are several types including X-linked (most common) with an incidence of 80% diagnosed with the syndrome, autosomal recessive at 15% and autosomal dominant at 5% [41]. It occurs due to mutations in the collagen. Specifically, the type IV, alpha5 (COL4A5) gene as a result of an X-linked semidominant condition. The COL4A5 gene encodes for type IV collagen and is responsible for one of six subunits which then form networks contributing to the structure of the basement membrane.[42] More severe effects may occur among males compared to females. Autosomal recessive mutations in COL4A3 or COL4A4 are seen in less than 10% of patients. Although in this form, both genders are affected severely[43]. It has an incidence of about 1:5,000 people [44]. The clinical manifestations that may occur as a result of the syndrome include hematuria, renal failure, hearing loss, renal flecks and lenticonus[45].

Genetic testing is highly recommended as the best form of diagnosis for patients. Treatment involves renin-angiotensin system blockade to treat autosomal recessive and male X-linked Alport syndrome individuals[46]. To manage the disease, focus is centered on preventing kidney failure. For patients progressing to final stages of kidney failure, transplants are advised.

Thin Basement Membrane Neuropathy

Thin Glomerular Basement Membrane

Thin basement membrane disease (TBMD), also known as benign familial hematuria or thin basement nephropathy, commonly causes hematuria, urine containing red blood cells. The condition causes diffuse thinning of the glomerular basement membrane in the kidneys. It is a disorder that affects 1% of the population and it is most commonly an inherited disorder[47]. Some evidence suggests that abnormalities of the basement membrane occur due to defects in type IV collagen genes COL4A3 & COL4A4. These genes are responsible for encoding alpha-3 & alpha-4 chains which are essential components in manufacturing type IV collagen. The disorder may occur in conjunction with Alport syndrome or IgA Nephropathy [48]. Individuals affected by this disorder generally have normal functioning kidneys, although some adults may develop renal failure. In most cases, it is often seen in patients who have a family history of hematuria. [49]

IgA nephropathy

IgA nephropathy, also known as Berger's syndrome, is the most common type of glomerulonephritis and end stage renal disorder [50]. The disorder involves immunoglobulin A (IgA) which attaches to the glomeruli and then progressively destroy it. The kidney will loose filtration function which can develop into chronic kidney failure. Treatment focuses on dialysis and transplants [51].

Diabetes

Diabetes mellitus is a metabolic condition that consists of causes including chronic hyperglycaemia, problems with metabolism of fat, carbohydrates, and protein along with insulin secretion problems. The disorder is responsible for affecting a number of organs, especially kidney function. It may contribute to other associated complications such as hypertension [52]. Diabetes affects the glomeruli. It degrades the filtration structure; therefore, normal function is altered [53]. This occurs due to microangiopathy in which the glomerular capillary and tubular basement membranes thicken and the mesangial matrix expands [54]. This may lead to kidney failure and even death. The end stage of renal disease occurs due to diabetic nephropathy onset which can be clinically accompanied by proteinuria, increased blood pressure and glomerular filtration impairment[55]. Patients are often advised to undergo dialysis, and in some severe cases kidney transplant.

Progression to Cancer

The endothelial basement membrane normally prevents migrating cells to enter by providing a barrier. However, metastic cells can invade the parenchyma of specific organs and proliferate causing a tumour to arise and metastasis. Enzymes which degrade the matrix have been identified in metastatic cells. These include serine proteases, cathepsins and metalloproteinases. Collagenase IV/gelatinase enzymes and serine proteases are also significant for the invasion of the basement membrane. [56].

Most cancers which become malignant have been identified to invade through the basement membrane. These include:

  • cervical
  • colorectal
  • Any epithelial derived cancers
Rare Abnormalities
Genetic

Epidermolysis bullosa

Epidermolysis Bullosa (EB) is a condition in which the skin becomes fragile. This makes the skin susceptible to injury which can cause painful blisters. This can become more problematic if the blisters become infected. Blisters may occur on the skin or inside the body in areas such as the mouth, oesophagus, stomach (GIT) or the bladder [57] . There are several types of EB. These include simplex EB, junctional EB, and dystrophic. The dystrophic type of EB is a hereditary disorder that causes blistering. It is an autosomal dominant disorder with recessive inheritance. It occurs due to type VII collagen gene mutations. This gene encodes collagen proteins which are components exhibiting fibril anchoring in dermal-epidermal junctions [58].

HANAC

Hereditary angiography with nephropathy, aneurysms and muscle cramps is caused by the heterozygous mutation in the COL4A1 gene. The syndrome is associated with blood vessel disorders. The vascular structures and basement membrane are weakened which then become susceptible to ruptures. Nephropathy may also occur when the basement membrane in the kidneys can cause hematuria. There may also be complications with the eyes, imparing normal vision. This involves dilations of arteries which can lead to bleeding causing cataract clouding. This disorder is one of the most uncommon autosomal dominant conditions and only several families have been identified to have been affected. Many parts of the body are affected because COL4A1 is responsible for type IV collagen which is necessary for basement membrane formation [59]. The membrane is seen throughout the body especially in the blood vessels. When type IV collagen is unable to develop, proteins in the basement membrane tissues, such as the brain, muscles, eyes and kidneys, may weaken [60].

Affects of Goodpasture's Disease showing glomerulonephritis and fluorescent staining of the glomerular basement membrane

Goodpasture's disease(anti-GBM)

Goodpasture's disease or anti-glomerular basement antibody disease(anti-GBM), is a vasculitis of the glomerular capillaries, pulmonary capillaries or even a combination of both[61]. The immune cells produce antibodies against collagen, thus, destroying collagen in the kidney and lung regions. The incidence of the disease is about 1 case in a million per year. It is diagnosed by the presence of the anti-GBM antibody within blood circulation or renal tissue. [62] Even though it is a very rare autoimmune disorder of a Goodpasture antigen, the anti-GBM antibodies have been identified as the noncollagenous-1 domain of the α3 chain. These involve the basement membrane collage type IV. It has also been noted that immune mechanisms consisting of both humoral and cellular types allow the disease to develop [63]. Treatment involves several techniques such as immunosuppressive medication (cyclophosphamide), ensuring the immune systems continues to produce antibodies. Corticosteroids are also used to suppress the autoimmune response in the body. Another method is Plasmapheresis which involves the removal of blood form the body. This ensures that anti-GBM antibodies are removed from the plasma. [64]

Cogan’s microcystic dystrophy

Cogan's microcystic dystrophy, also know as epithelial basement membrane dystrophy (EBMD) or Map-dot-fingerprint dystrophy, is a condition that affects the cornea of the eyes. Anterior corneal dystrophy occurs bilaterally, featuring epithelial grey lines and dots (microcysts). The microcysts occlude the cornea which can cause irritation to the ocular lens. This will cause it to become inflamed, impairing vision [65]. Patients are usually asymptomatic although they can exhibit painful and recurrent corneal erosion, decreased vision, and photophobia. Recurrent erosion may occur due to insufficient adhesion in basal epithelium to abnormal lamellar structures [66].

[67] [68]

Current Research

For further information on what is currently going on in the field of cell biology regarding the basement membrane, take a look at the following recent articles published to PubMed:

Piero Papi, Stefano Di Carlo, Daniele Rosella, Francesca De Angelis, Mario Capogreco, Giorgio Pompa Peri-implantitis and extracellular matrix antibodies: A case-control study. Eur J Dent: 2017, 11(3);340-344 PubMed 28932144

Isha Sharma, Rashmi S Tupe, Aryana K Wallner, Yashpal S Kanwar CONTRIBUTION OF MYO-INOSITOL OXYGENASE IN AGE: RAGE MEDIATED RENAL TUBULO-INTERSTITIAL INJURY IN THE CONTEXT OF DIABETIC NEPHROPATHY. Am. J. Physiol. Renal Physiol.: 2017;ajprenal.00434.2017 PubMed 28931523

Linxi Li, Ying Gao, Haiqi Chen, Tito Jesus, Elizabeth Tang, Nan Li, Qingquan Lian, Ren-Shan Ge, C Yan Cheng Cell polarity, cell adhesion, and spermatogenesis: role of cytoskeletons. F1000Res: 2017, 6;1565 PubMed 28928959

Yaojun Zhang, Shaoyan Xi, Jinbin Chen, Dongsheng Zhou, Hengjun Gao, Zhongguo Zhou, Li Xu, Minshan Chen Overexpression of LAMC1 predicts poor prognosis and enhances tumor cell invasion and migration in hepatocellular carcinoma. J Cancer: 2017, 8(15);2992-3000 PubMed 28928891

Anu Hyysalo, Mervi Ristola, Meeri E-L Mäkinen, Sergei Häyrynen, Matti Nykter, Susanna Narkilahti Laminin α5 substrates promote survival, network formation and functional development of human pluripotent stem cell-derived neurons in vitro. Stem Cell Res: 2017, 24;118-127 PubMed 28926760


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