THIS LECTURE HAS AN OUTCOMES SLIDE, SO I ACTUALLY KNOW WHAT I NEED TO FOCUS ON!!! A-fucking-mazing.
Liver as an organ- Function and structure
See previous post: Digestion and Absorption of Food- Part 2
The liver is made up of two lobes, which can be further subdivided into small lobules. Each lobule is made up of a central vein, sinusoids, canaliculi and hepatocytes. Blood from the portal vein and hepatic artery flow through sinusoids into the central vein, the hepatocytes produce bile, and the canaliculi take bile to the bile duct. The canal of Hering is the junction between hepatocytes and bile ducts. Other cells present include endothelial cells, which line sinusoids (remember, they're basically just giant blood vessels) and Kupffer cells (which are basically macrophages in the lumen of sinusoids).
One of the most remarkable features of the liver is its ability to regenerate itself. When the liver is damaged in some way, gut-derived factors such as LPS (lipopolysaccharide) are upregulated. LPS activates Kupffer cells, which release pro-inflammatory cytokines, such as IL-6 and TNFα. The pancreas, duodenum, salivary gland and others also release a bunch of factors, which allow the hepatocytes to continue dividing. At the same time, TGFβ, an anti-inflammatory cytokine that inhibits hepatocyte DNA synthesis, is blocked.
Liver Disease
Disease progression
In early stages of liver disease, fat can build up in your liver, resulting in non-alcoholic fatty liver disease (NAFLD). Later on, this fat can become inflamed and liver cells can be damaged, resulting in non-alcoholic steatohepatitis (NASH). NASH can then result in cirrhosis (scarring of the liver). Cirrhosis, in turn, can lead to hepatocellular carcinoma or death unless a transplant is done.
Current treatment options
In early stages of liver disease, the damaged parts can simply be removed, and the healthy liver allowed to grow back. Unfortunately, it is very difficult to detect early liver disease. If the disease isn't detected until later, then a transplant is necessary, but unfortunately demand far outstrips supply. Patients who have acquired hepatocellular carcinoma (HCC) may undergo a partial hepatectomy (removal of part of the liver), transplantation, radiotherapy, or take Sorafinib, but prognosis is still very poor.
Regenerative Medicine and Cell Therapy
ELAD
ELAD, or extracorporeal liver-assist device, has four cartridges containing human liver cells. A patient's plasma passes through these cartridges, allowing for transfer of toxins, metabolites, and so forth. ELAD is currently on a phase III clinical trial.
Stem Cells – what stem cells are
OH I FUCKING WONDER. I certainly haven't spoken about them here, or here, or here, or here, or here, or here, or here...
Liver Stem Cells / progenitor cells
We still aren't 100% sure which cells serve as liver stem cells, but oval cells seem to be good candidates. Oval cells are oval shaped (BET YOU DIDN'T SEE THAT ONE COMING!) and grow as extensions of terminal biliary ductules in the liver. They form ductular structures that communicate with the biliary system at one end and form hepatocytes at their other end. The interesting part about oval cells is that they are induced as liver damage proceeds, and appear to be able to produce both hepatic cells and cholangiocytes (epithelial cells of the bile duct).
Cholangiocytes themselves may be able to act as liver stem cells. It has been shown that cholangiocytes can differentiate to produce hepatocytes, but this may only be possible when hepatocyte differentiation is inhibited.
Using LPC to treat disease
Tyrosinemia Type I
Tyrosinemia is a genetic disorder in which the FAH gene is mutated. The FAH gene codes for FAA hydrolase, which is one of the enzymes involved in the breakdown of tyrosine. In untreated tyrosinemia, tyrosine and its byproducts build up in tissues and organs. Interestingly enough, transplanted liver progenitor cells (LPCs) (which I'm assuming are oval cells?) are able to express FAH, at least in mice.
Methylmalonyl Aciduria (MMA)
I've discussed MMA before on my blog. Essentially, it is a defect in methylmalonyl CoA mutase, which leads to the toxic build-up of methylmalonic acid in the blood. Children with MMA are low weight for their age, and mortality is high due to toxicity. MMA can be treated with a liver transplant, but LPCs might be able to help too.
Gene Correction
Gene correction is another technique that is being studied. The idea is that if we can take a patient's cells, turn them into iPS cells, "correct" the defective genes by using gene technology, and then growing and differentiating the "corrected" cells, we can treat genetic illnesses. Gene technologies that can be used include viral vectors, such as the Adeno-associated virus (AAV) vector, and the CRISPR Cas9 method. There appears to have been some success in using AAV vectors to treat haemophilia, but for most diseases we haven't gotten anywhere near that stage yet. iPS cells produced with this technique can also be exposed to different drugs in order to find an effective drug- essentially personalised medicine.
Liver Organoids
Some work has been done in growing mini livers. Two cell types are required: LPCs and endothelial cells (for the blood vessels). These cells need to be grown on a scaffold, along with a third type of cell, which is taken from fat left over from reconstructive surgery.
Liver Progenitor Cells and Cancer
Unfortunately, LPCs do come with a risk of fibrosis and cancer. LPCs have been implicated in liver hepatocellular carcinoma, which is rather unfortunate, given that liver hepatocellular carcinoma was one of the outcomes that we were trying to avoid in the first place! Oh well.
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