welcome to the da vinci academy histology video course the entire video course is available on youtube and covers all of the fundamental principles of histology and relevant cell biology you can find all the videos from the course by clicking the histology playlist link in the description below and then you can access the corresponding practice questions and histology lab videos by going to our website which is also linked in the description below in this segment we'll discuss what's holding the epithelial tissues together as well as holding it to the underlying connective tissue let's turn our attention now to the all-important cell cell junctions of the epithelia we'll start with the occluding junctions also known as the tight junctions also known as the zonula occludens these are just three different names for the same thing there's a lot of these in histology so welcome and watch out for them well the tight junctions are located on the apical regions of the lateral cell membranes we have to remember that the cells are actually three-dimensional so the tight junctions actually go all the way around the periphery of the cell membrane much like a belt like so and when we zoom in onto one of these regions where the tight junction is coming together between the two neighboring cells we'll see one cell membrane here one cell membrane from the neighboring cell and kind of bound within the cell membrane of one cell we see these protein complexes made up of lots of different proteins but we'll name just two occludens is one type and claudin's is the other type these protein complexes from one cell membrane will fuse pretty tightly with the protein complexes from the neighboring cell like so essentially forming a seal much like a ziploc bag between the two cell membranes and what that does is that it prevents any large molecules like a glucose or any charged molecules like sodium ion or something like that from traveling in between the two cell membranes a space called paracellular space so this paracellular space essentially sealed up and inaccessible by these large molecules or charged molecules which means the only way for these large molecules to get into the underlying connective tissue is through the epithelial cell via intracellular transport so super important for the filtration function and protective function of the epithelium another function of the occluding junctions is to contribute to the apical membrane specialization what that means is that the proteins that are that are expressed on the apical surface may be different from the proteins that are kind of on the lateral and basal surfaces of the same cell and you may actually remember that the cell membrane is really comprised of this fluid mosaic of phospholipid bilayers with number of proteins kind of embedded and these proteins can easily float in any direction within the membrane but when there is an occluding junction it prevents the protein from passing through these tight junctions so any protein that is meant to be on the lateral surface can't get up onto the apical surface where they're useless and likewise any proteins that's on the apical side something like receptors that are only useful on the apical side cannot get back down to the lateral surface either so membrane specialization is very important for the proper functioning of the epithelia as well knowing all these functions let's see if we can predict the consequences of any aberrant expressions of claudines or or occludens that may weaken the occluding junctions and the result of weakened tight junctions could be that these large molecules can easily transport or pass through in between the cells into the connective tissue the paracellular movements of macromolecules is a bad news in that we could be losing lots of nutritious molecules like glucose to the outside environment or large pathogens from the outside environment can easily gain access to our connective tissue essentially into our body so tight junctions very important for sealing up our body next we have the adherence junctions or also known as the zonulae adherence the adherence junctions are positioned just below the occluding junctions and much like the occluding junctions these adherence junctions will go all the way around the cell membrane and its periphery much like a belt and again they're positioned just below the tight junction if i may draw that in here so their function really is to stabilize the occluding junctions that are just above them and that has to do with the fact the occluding junctions are structurally speaking fairly weak so it requires some level of stability provided by the adherence junctions and when we look at the adherence junctions where the two cell membranes come together where here's one cell membrane another cell membrane from the neighboring cell what we see are these transmembrane proteins called the cadherins that interdigitate with the cadherin from the neighboring cell membrane like so so the physical contact or the structural support is provided by the interdigitation of the adherence but as you can see there these interactions are not like the occluding junctions where the cells are physically being sealed together so there's actually a lot of paracellular space here so without the occluding junctions we would have this terrible paracellular transport of macromolecules occurring intracellularly there are all these actin fibers that are attached to the intracellular aspects of the cadherins these actin fibers tend to kind of dissipate the force that may have been applied at the cadherins away and in that way the adherence junctions have some substance and and structural integrity that can then support the stability of the occluding junctions above so knowing these functions of the adherence junctions let's predict some consequences of weakened adherence junctions well weakened adherence junction would mean weakened tight junctions or occluding junctions which then could potentially allow paracellular transport of macromolecules which is something that we're trying to avoid next we have desmosomes also known as the immaculate adherence macula stands for a spot and adherence stands for the adhesions so desmosomes are these spot-like adhesions between the neighboring cells as opposed to being a belt-like structures like the zonulae adherence the desmosomes are also located below the level of the zonula adherence but they're still on the lateral aspects of the cell membrane and there's usually a number of these spot adhesion sites that's holding the neighboring cells together so number wise and strength wise desmosomes play perhaps the most important role in cell cell attachments much like the zonula adherence the desmosomes utilize the catherine proteins so these are the transmembrane proteins that extend out into the paracellular space and interdigitate or make a bond with the paracellular aspect of the cadherin from the neighboring cells the intracellular aspect of the cadherins in the desmosomes however are strongly attached to and are reinforced by a complex of of proteins collectively called the attachment plague and although there are many different types of proteins that make up this plaque we'll tell you about just the two we have the desmoplaquen and placoglobins globins is the other type of proteins the attachment plaque in addition to anchoring the cadherins they have the intermediate filaments the cytoskeletal components that are stronger than the actin fibers that come and attach to the attachment leg and because the desmosomes are reinforced by stronger filaments the desmosomes can withstand bigger forces applied to the cadherin interdigitations and intermediate filaments are able to disperse bigger force that's applied to this attachment plaque i like to compare the desmosomes to a numerous velcro spots that's present in between the two cell membranes as opposed to a really thin strip of velcros that go around the periphery of the cell like the zonular adherences and much like the velcro there's plenty of space in the paracellular aspect in between the cell membranes so desmosomes much like the zonular adherence are not very good at stopping any paracellular transport of macromolecules only the tight junctions can do that function now having learned the functions of the desmosomes let's predict some consequences of weakened desmosomes in an epithelial tissue well since the desmosomes play the most significant role in cell cell attachments to each other we can imagine that weakened desmosomes may cause the intra-epithelial lesions or the epithelial cells kind of separating away from each other with minor trauma there is actually a clinical condition called the pemphigus bulgaris this condition affects the covering epithelia of the the mucous membrane like the oral cavity as well as the skin where the epithelial tissue integrity is weakened by an autoimmune reaction the antibodies can attack one of these attachment legs and weaken the desmosomes here's histopathology of pemphigus vulgaris and here we can actually identify the epithelial tissue up here and we can recognize this as an epithelium because this tissue has lots and lots of cells and very little ecm a lot of nuclei that are crowded together and it sits on top of this basement membrane and it seems like the interface between the epithelium and the and the connective tissue is kind of undulating which is typical of a tissue like the epithelium and mucosa and under here is our connective tissue and within the epithelial tissue we can appreciate these tears where epithelial tissue itself is lifted away from each other therefore we have these intra-epithelial lesions that are present within the epithelial tissue itself so weakened desmosomes can have such a significant clinical consequence and next we have the gap junctions the gap junctions are comprised of the monomer proteins called the connections these connections are shaped like a little three-dimensional wedge like so and imagine about six or so of these connections coming together in three dimension and forming a barrel shaped protein complex with a pore or channel in the middle so this protein complex now is called the connexon the connexon is of course embedded within the cell membrane of an epithelial cell then the connexon of another epithelial cell membrane will come and bind to the first connexon therefore now we have a continuous channel or tunnel or pore between the two epithelial cells so for this reason the gap junctions are sometimes also called as the communicating junctions so gap junctions can then allow this rapid intracellular exchange of materials between the epithelial cells which would come in handy in the avascular epithelial tissues and in large numbers the gap junctions can actually facilitate the formation of the cytoplasmic sensation meaning that number of these epithelial cells can function as a single unit and now onto the cell and the connective tissue junctions or more specifically the cell to the ecm junctions which are the hemidesmosomes the hemidesmosomes are physically located on the basal surface of the cell the part that's sitting on top of the basal lamina so this would be the apical surface lateral surface here now we're talking about the basal surface of the epithelial cells hemi refers to a half and we've already learned about the desmosomes which are located on the lateral surfaces so we're talking about half a desmosome that is positioned on the basal cell membrane so physically hemidesmosomes structurally are very similar to that of the desmosome except that there's only half of it at least the part that belongs to the cell does so there is a transmembranous protein that extends out into the ecm and then intracellularly there are these protein complexes that's anchoring the transmembranous protein and forming an attachment plaque here and furthermore we have all these intermediate fibers or filaments that's reinforcing this entire structure so that's hemi desmosome and what this hemidesmosome binds to is the basal lamina which is the ecm that is produced and secreted by the epithelial cells themselves in terms of the transmembranous proteins the hemidesmosomes use proteins called the integrins rather than the cadherins the integrins are structurally similar to that of the cadherins but they're more specialized to bind to these high molecular weight extracellular matrix proteins called the laminins which themselves then are embedded into more substantial protein filaments down here so it's the strong interactions between the integrands and the laminates that are reinforced by the intracellular components as well as the basal lamina components that's holding the epithelial tissue tightly onto the basal lamina then to the basement membrane then to the connective tissue so knowing the structures and the functions of the hemidesmosomes let's predict some consequences of the weakened hemidesmosomes well there's a clinical condition called the bullish pemphigoid where this actually happens usually due to some drug reaction or it could be due to inappropriate antibody recognition of any one of these proteins that may cause the entire epithelium to lift off of the basement membrane and away from the connective tissue and here's the histopathology of that condition here we have the epithelial tissue we recognize it by the crowding of number of these cells a bunch of cells with their nuclei and we're seeing very little ecm in between suggesting that we're looking at the epithelium and then here's the connective tissue which has you know some scattering of cells here and there we're mostly looking at the basophilic nuclei staining and lots of ecm components perhaps fibers and things like that and in between the epithelium and the connective tissue we have this large lesion or defect where the epithelium is lifted off of the connective tissue this condition is the booleas pemphigoid which is to be distinguished from the desmosomal lesion or intra-epithelial lesion that we saw earlier which is the pemphigus bulgaris and in those cases we would have the intra-epithelial lesion like that so that's one of the conditions and another kind of clinical implication of the hemidesmosomes would be the fact that when cancer cells or tumor cells start to invade and migrate into the underlying connective tissue it usually involves disintegration of the hemidesmosomes as well as the desmosomes really that causes the breakdown of the basement membrane in order for the cancer cells to migrate down into the connective tissue and then metastasize so these cell cell junctions and the cell to connective tissue junctions have pretty important implications in tumor invasion migration and metastasis as well all right now before we move on to the rest of the epithelial lecture let's clarify these two terms the basal lamina in the basement membrane you may have noticed that we've been using these two terms interchangeably and that's an okay practice a lot of textbooks do it as well as other educators but there are some subtle differences that may come in handy as a future reference basal lamina basement membrane they both refer to the acellular extracellular matrix that's positioned between the epithelial tissue and the connective tissue but when we look at the ecm in higher magnification with say transmission electron microscopy we see that there are actually three layers of materials that's forming the ecm first we have the basal lamina this layer is secreted by the epithelial cells themselves basal lamina upon higher magnification we can see that is comprised of two sublayers the lamina lucida and lamina densa lamina refers to layers lucida refers to lucid so we're talking about electron light area and densa refers to electron dense area lamina lucida is positioned just under the epithelial cell itself and this is where a lot of laminins are found that contribute to the hemidesmosome anchoring or attachment and these laminins are actually anchored to the electron dense area called the lamina densa where a lot of more fibular proteins are kind of concentrated here anchoring the laminans and below the lamina densa there's an extra layer of stuff called lamina reticularis so this is reticular fiber rich layer and this layer tends to be much thicker than the basal lamina so lots of reticular fibers and these fibers are not produced by the epithelial cells but instead by the fibroblasts in the connective tissue these particular fibers again are kind of packed up right up against the lamina densa so when we are talking about the basement membrane we're actually talking about the base basal lamina plus the lamina reticularis together is what forms the basement membrane so since basal lamina is a part of the basement membrane we can see how using these two terms interchangeably would be an okay practice although technically basal lamina is a subunit of the basement membrane here's an electron microscopy of the basal lamina in the basement membrane first here's the epithelial cell and all of these electron dense region is the nucleus of the epithelial cell and i'm now outlining the basal cell membrane of the epithelial cell and as i trace the basal cell membrane you'll start to notice that there are these electron dense regions along the basal cell membrane these are the hemidesmosomes and they are looking more electron dense because there's a lot of attachment plagues as well as the intermediate filaments that are anchored to it thus making these regions more electron dense under the basal cell membranes now we're starting to see these electron light areas that i'm highlighting with yellow color this area is electron light so this is the lamina lucida and under the lamina lucida we're now seeing an electron dense region really thin and it's actually highlighted by these arrow points of these arrows these electron dense areas are the lamina densa and it's the lamina densa and lucida that's forming the basal lamina and then even below the the lamina densa we're seeing this region where we have these fuzzy fibers that are positioned here these are all reticular fibers so this is the lamina reticularis which means the basement membrane is really perhaps this thick it contains the basal lamina and then lamina reticularis together now under the light microscopy it's really the basement membrane that we are able to see not the basal lamina the basal lamina is too thin for us to resolve with standard light microscopy so again it's easy to see why we're using the term basement membrane to refer to all of these ecm together but basal lamina has a different meaning because it's a two sub layers that's exclusively produced by the epithelial cells themselves in this segment of epithelial tissues lecture series we discuss the cell cell junctions and the cell to connective tissue junctions which largely involve the lateral and basal cell membranes in the next part of this lecture series we'll discuss some specializations of the apical cell surface and practice epithelial tissue pattern recognition thank you for watching this video from the da vinci academy histology video course which is completely available on youtube to access the corresponding practice questions and histology lab videos go to our website using the link in the description below foreign [Music] so [Music] you