The who’s who of liver cells

TRISH LALOR: In this activity, we are going to introduce you to some of the key cell types that reside within your liver. This is so we can explain what they all do, and importantly, how things change in liver disease. This will help you to understand some of the tests for liver function that we describe later on, and also some of the structures and cell types that our surgeons and clinical colleagues talk about later in the course. In particular, our liver pathologist, Professor Stefan Hubscher, will show you how the liver appears under the microscope when a transplanted organ is being rejected. By this, we mean when the patient’s immune system recognises the foreign transplanted tissue and begins to destroy it.

So it’s important that we understand the basic structure of the healthy liver first. Let’s start by looking at a healthy liver under the microscope. This is an example of a normal liver that was collected for transplantation but not used. This sometimes is because a clinical team noticed an abnormality in the donor liver, maybe an unexpected lesion or too much fat in the tissue that would stop it working properly, or there’s some other functional indication that they’re worried about. In this case, the donor’s family may give consent for the organ to be utilised for research rather than not being used.

Generous donations such as this are one of the reasons that our research group in Birmingham is able to do the ground-breaking clinical research and teaching that we do. Now, this section has been cut very thin, about 5 micrometres or 1/10 of the thickness of a hair, and stained with chemical dyes that allow us to see the individual cells. One of the dyes in this stain, which is called a Van Gieson stain, makes collagen or connective tissue appear red. You can see this indicated by the white arrows on this image.

In a normal liver like this one, the connective tissue or extracellular matrix is there to provide a structure for the cells to sit in and also to provide support for tubular structures like blood vessels. So there is not much red staining in this sample apart from around those vessels and bile ducts. The rest of the tissue stains a brownish colour with this dye, and you can see the nuclei of the cells– those are the bits which control the genetic information and the cell itself– stained a slightly darker brown. I’ve also indicated some of these with white arrows here. So let’s think about some of the specific cells you can see in this image.

This liver has been stained with another common stain called hematoxylin and eosin to show you the hepatocytes. These are a typical epithelial cell or barrier cell, and they make up about 80% of the volume of the liver. They’re 20 to 40 micrometres across, which is about half of the thickness of a hair. These are the cells that make bile, store vitamins and fat, make important proteins, secrete glucose, and are also involved in detoxification and metabolism. Our next cells are another epithelial population, this time the biliary epithelial cells, which make up about 1% to 3% of your liver tissue. These cells are labelled with a white arrow in the image shown here. They look a bit like a string of beads.

They make up the biliary channels or bile ducts, which can range in size from tiny little structures of the portal areas to great big tubes which drain out into your gallbladder. And these cells exchange materials to and from the bile, things like water and bile salts for recycling. You can also see three other major structures in this picture, one on either side of the bile duct and the big vessel below it. These are all blood vessels, and this area where they all enter the liver is called a portal tract. You can see two branches of the hepatic artery, which brings oxygenated blood into the liver. And these are indicated by black arrows. And also the portal vein below these.

This is the big vessel which brings blood from the intestines to the liver. All of these vessels are lined by another epithelial cell population called endothelial cells. There are also capillary like channels called sinusoids, which are another endothelial-lined lined blood vessel there to ensure that there is a maximal exchange of blood contents to and from the liver. This makes sure that cells like the hepatocytes are abundantly supplied with oxygen, and also that anything they might make, such as the albumen and clotting factors we mentioned before, are easily secreted into blood.

In this next image, you can see the edge of another of these portal areas, where the blood comes into the liver. But this time, I’ve indicated the little group of cells that look like black spots in the bottom of the picture. These are white blood cells, which sit inside the liver to protect it from any bacteria or viruses. So they tend to sit around those areas where the blood comes into the tissue to deal with any problems. There are several different white blood cell types, which can either engulf or eat pathogens like bacteria to kill them, or they can kill infected or tumour cells, or they can secrete compounds which direct other cell populations to deal with a problem.

In disease, the number of white cells increases rapidly in the liver to fight infection with something like a hepatitis virus, for example. These cells are really important in the context of transplantation, so you will hear more about them later this week and also when we talk about organ rejection later in the course.

Now, the next cell I would like to introduce you to is very important in a process called fibrosis that you may have heard of. These so-called stellate cells sit inside those sinusoidal capillaries I mentioned earlier, some of which I’ve indicated here with white arrows. The image next to the arrows shows the stellate cells, which are labelled HSC for Hepatic Stellate Cells. And they’re sitting next to a red vessel, which is lined by Endothelial Cells, or EC. The stellate cells are star-shaped cells– hence the name– which sit between the hepatocytes and endothelium like the filling in a sandwich. In health, they store useful fats or retinoids like vitamin A, which are used to regulate liver growth and function.

This is indicated by the white bubbles in the picture. However, in response to liver injury, these cells change dramatically. They lose this retinoid and begin to proliferate fast, so they increase in number. More importantly, they secrete a lot of extracellular matrix proteins, like the red collagen we talked about in our first picture of the normal liver.

Now, if you look at this next image of a seriously diseased or cirrhotic liver, this graphically shows you this build-up of connective tissue in red. As you can see, when those stellate cells are activated in disease, you get this enormous increase in matrix production, which compromises the rest of the tissue. There aren’t many hepatocytes left to fill in all those essential functions that we described earlier. And also, that build-up of scar tissue, or fibrosis, makes the liver very hard and shrunken and restricts the flow of blood through it. You can also see that this liver is quite inflamed, as there are a lot more of those white blood cells in this sample, which I’ve indicated by the white arrow.

Now, this change in texture and function of the liver in disease causes a lot of problems that are commonly faced by patients with end stage liver failure who need a transplant. The build-up of pressure in the liver forces tissue fluid out into the abdomen. This is called ascites and is very uncomfortable and needs to be drained regularly. The increased blood pressure or portal hypertension within the cirrhotic liver also can cause upsets in the blood supply to other organs, such as a kidney, so then you might see renal damage too. And you can also develop bulging vessels or varices in the oesophagus in this situation. And these vessels can sometimes burst to cause dramatic blood loss in some patients.

This is a very serious complication of cirrhosis. In addition, the lack of functionally capable liver mass due to that build-up of scar tissue where the hepatocyte should be means that key detoxification processes are not carried out efficiently. There can be impaired removal of toxic compounds like ammonia from the blood, and this can then travel to the brain and cause swelling and neurological symptoms, or even coma. And this is called hepatic encephalopathy. OK, so that’s the major cells that make up the liver covered, and we’ve also touched on some key processes that we’ll pick up on later in our discussions of liver disease and symptoms.

In our next activities, we’ll talk a bit more about both the plumbing of the liver, or the blood and bile supply, as well as key populations of immune cells.