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Related to my earlier question, "How does the human liver regrow?", am curious as to why the liver is the only major organ that has this capability?
Why is it that other major organs, such as the heart and lungs etc are not able to regrow in the same fashion?
Maybe it is due to two factors:
The liver is one of the few solid non-tubular organs. If a tubular organ is damaged, all the layers that composes it must regenerate. This layers usually have different cell types, which is always nasty for regeneration since some of them may be formed by specialized tissue (for instance, myocytes are very difficult to regenerate. If the organ has a muscle layer, such as the esophagus, regeneration will be more difficult). Furthermore, damage in a tubular organ usually involves perforation, which will disrupt its function even if the injure isn't big.
Hepatocytes are pretty undifferentiated cells. They are basically enzymatic sacks with some vacuoles and mitochondrion, but they remain as your typical animal cell. They have a regular nucleus, they don't have any cytoskeletal adaptation and their vacuoles don't compose the most part of their cytoplasm (in a healthy liver). Cells with so little morphological specialization usually regenerate with no problem. Plus, the liver itself is constantly exposed to chemical damage due to toxins, drugs and other chemical compounds that may be present in the diet. This situation is special and don't apply for any other organs, with the exception of the kidneys (which, in fact is a very complicated tubular organ).
It helps to think about why it's beneficial for an organ/tissue to regenerate. The liver is your main detoxifying organ. It does this by chemically modifying external (and internal) molecules to counter their possible bad effects or simply to be able to excrete them. This role brings liver cells in harms way. Take paracetamol for example. It is recognized as a foreign compound and detoxified mainly in the liver. If you overdose like many unfortunately do, liver cells are the first to die. So, to keep up your defenses the body has activated regeneration in liver cells but not in many other parts of the body that are more safely tucked away.
That said, many other organs and tissues in the body constantly regenerate too. The intestinal tract constantly produces new surface cells from stem cells that lie deeper down in the organ because it also is on the front lines just like liver cells. Something similar is true for the skin but of course skin and gut are both external organs and therefore closer to our environment. The liver is not far off, because it is among the first organs to receive blood from the intestine.
So even though it is possible to induce regeneration in many cells of our bodies artificially as induced pluripotent stem cells have shown, evolution has switched this on only in a few of our cell types which require more renewal than others, hepatocytes included.
Liver regeneration may be simpler than previously thought
The way the liver renews itself may be simpler than what scientists had been assuming. A new study, appearing in the April 13 issue of The Journal of Biological Chemistry, provides new information on the inner workings of cells from regenerating livers that could significantly affect the way physicians make livers regrow in patients with liver diseases such as cirrhosis, hepatitis, or cancer.
"The human liver is one of the few organs in the body that can regenerate from as little as 25 percent of its tissue," says Seth Karp, assistant professor of surgery at Harvard Medical School, Boston, and main author of the study. "It is not known how the liver does it, but our results provide some details of what makes the liver so unique."
Although organ regeneration has been observed in many animals, the details of how it happens at the cellular level are still not completely understood. So far, scientists have shown that cells that participate in tissue regeneration behave as if they were part of a growing organ in an embryo. In other words, the cells act as if the liver is growing, as do other organs in a developing embryo.
Many of the proteins that induce organ regeneration have been identified and scientists are now trying to make organs regrow by stimulating these proteins. Regrowing livers this way would be especially useful for patients whose livers are so damaged -- say, by a tumor that has spread to most of the liver -- that a large part would be removed. Unless such patients receive the right amount of liver transplant from an organ donor, they do not always survive. Quickly stimulating the growth of the remaining portion of their liver could be their only chance of survival.
To investigate how the liver regenerates, Karp and his colleagues set out to determine which proteins are involved in the regenerating cells. The scientists were also interested in testing whether regenerating cells behave like embryonic ones, as is commonly assumed for other organs. New processes may explain why the liver is so uniquely capable of renewal and repair after injury, the scientists thought.
Karp's team considered two samples of mice. The first consisted of embryonic mice at various stages of development while the second was composed of adult mice to which two-thirds of their liver were removed. Using techniques such as DNA microarrays -- which determine which genes are active in a cells -- and software programs that analyze the collected information, the scientists listed all the proteins that help the cells grow and proliferate in both samples.
The results were unexpected. The researchers noticed that only a few proteins were common to both processes. Proteins called transcription factors, which affect DNA in the cell's nucleus, were highly involved in the development of embryos' livers but not in adult liver regeneration. Instead, proteins that help cells proliferate were active in both the developing and regenerating livers.
These findings showed that a regenerating liver does not behave as a developing embryo. Instead, regeneration could actually be only due to an increase in cells that multiply through regular cell divisions, a process called hyperplasia.
The new results may also have important medical implications. Transcription factors are known to be more difficult to manipulate than the other identified proteins. Since the transcription factors were not present in regenerating livers, it might be easier to stimulate liver regeneration by only activating the other identified proteins.
"These results are very encouraging," Karp says. "Not only did we discover that the number of proteins involved in liver regeneration is relatively low, but they don't include transcription factors, so we may be closer to being able to stimulate liver regeneration than we thought."
The next step will be for scientists to understand whether the regenerating cells are stem cells. Studies have shown that adult stem cells are involved in the repair of many organs, but in the case of the liver, the cells repairing it through regeneration may simply be regular cells, not stem cells.
"We think that the liver regrows through a relatively simple process, which could explain its prodigious ability to repair itself," Karp says.
Article: "Restoration of Liver Mass after Injury Requires Proliferative and Not Embryonic Transcriptional Patterns" by Hasan H. Otu, Kamila Naxerova, Karen Ho, Handan Can, Nicole Nesbitt, Towia A. Libermann, and Seth J. Karp
Understanding the mechanisms of liver regeneration through computer simulation
How does the liver manage to regenerate itself even after severe damage? Seeking to find an answer to this significant medical question, scientists of the HepatoSys/German Virtual Liver Network have gained new insights into the underlying processes involved in the regeneration of liver lobules using computer simulation and laboratory experiments.
What that looks like has been demonstrated at the third Conference on Systems Biology of Mammalian Cells (SBMC) from June 3-5, 2010 at the Concert Hall (Konzerthaus) in Freiburg (http://www.sbmc2010.de). The new perspectives on liver regeneration open the door to developing new treatments for cirrhosis and other injuries to this vital organ.
The singular mechanisms of liver regeneration
The liver is a very special organ: even if more than fifty percent of its overall mass is damaged -- for instance, by intoxication -- it can regenerate itself completely. This amazing ability is essential. The liver is the body's most important metabolic organ and has the task, among others, of detoxifying the blood. To enable it to do this, the liver is equipped with a very complex anatomy: in humans both hepatic lobes are composed of about a million small lobules that are a maximum of one to two millimeters in size.
The blood flowing into the liver enters the lobules via the so-called portal field, which separates neighboring lobules from each other. From there it flows through microvessels surrounded by hepatocytes -- the most common type of cell in the liver -- and drains into a centrally located vein. This special architecture ensures that the blood is brought into optimal contact with the hepatocytes when it flows through the organ.
When a liver has recovered after damage caused by drugs, alcohol consumption or a viral infection, this complex architecture must be restored. The underlying mechanisms are still poorly understood. HepatoSys researchers led by Dirk Drasdo at the Interdisciplinary Centre for Bioinformatics in Leipzig (IZBI) and the French National Institute for Research in Computer Science and Control (INRIA) in Le Chesnay near Paris have started investigating liver regeneration using computer-based methods of systems biology: Drasdo and his team simulated the scenario after intoxication with carbon tetrachloride (CCl4) in mice -- a typical animal model for paracetamol intoxication in humans -- on the computer.
From the tissue section to the computer
The first of three steps was to obtain a computer representation of an average liver lobule. Working closely with the experimental research group led by Jan Hengstler of the Leibniz Institute and the University of Dortmund, the scientists recorded parameters necessary to quantitatively characterize the static lobule architecture, such as the shape and orientation of the blood vessels, and the shape, orientation and spatial organization of the hepatocytes. These parameters were extracted using image processing methods that allow the full three-dimensional reconstruction of microscopic images of specially prepared serial tissue sections, followed by turning the three-dimensional patterns into numbers.
The second step was to record the regeneration process in the liver lobules of mice. The animals were injected with the liver-damaging substance carbon tetrachloride, which -- like paracetamol intoxication -- results in the death of hepatocytes near the central vein of the liver lobule. To characterize the regeneration process quantitatively, the scientists introduced so-called process parameters. These parameters -- also obtained from image analysis -- record when and where new hepatocytes are created and register their movements and alignment within the organ in the process of regenerating the original architecture of the liver lobule.
Finally, based on all these parameters a mathematical model was developed with which the spatial- temporal dynamics of individual hepatocytes and blood vessels could be simulated on a computer. With their computer model the scientists managed to identify previously unrecognized mechanisms during regeneration in liver lobules. As it turned out, the new cells do not just emerge at arbitrary locations within the lobule "Instead it quickly became evident that the spatio-temporal process can only function properly if the new hepatocytes align themselves along the sinusoids, the micro-blood vessels that traverse the liver lobule," explains Drasdo's co-worker Stefan Höhme. This observation on the basis of the computer model was subsequently confirmed on real liver lobules in a laboratory experiment. "That," according to Höhme, "brings us closer to an understanding of the complex processes involved in liver regeneration."
Not only for the liver
As Drasdo emphasizes, such a dynamic model of a multi-cellular arrangement capable of making correct predictions is still a great exception: "It simultaneously records single cells and the whole tissue," he says. "And that creates the basis for examining in more detail the signalling processes within and among the cells that control regeneration."
Chronic liver disease: how could regenerative medicine help?
Chronic liver disease is the fifth biggest killer in the EU. Once serious damage has been done to the liver, it loses the ability to repair itself and this is a life-threatening problem. The only treatment currently available is a liver transplant. Could regenerative medicine help?
What do we know? ▼
The liver is the only internal organ in the human body capable of regenerating itself after being damaged.
In chronic liver disease, damage to the liver over long periods of time leads to the accumulation of scar tissue that limits the ability of the liver to function and repair itself. This disease is the fifth largest killer in the EU and presently can only be treated with liver transplants.
Researchers have successfully used embryonic stem cells and induced pluripotent stem cells to make new liver cells in laboratories, which may potentially be used to treat liver disease in the future.
What are researchers investigating? ▼
Researchers want to learn how stem cells in the liver are able to regenerate liver tissue. It may be possible to develop treatments that harness the natural ability of liver stem cells to regenerate the liver. Treatments using pluripotent stem cells to create new liver cells for transplantation into the liver are being developed.
Researchers are also developing bio-artificial liver devices and methods to bioengineer livers for transplantation.
Studies are also currently exploring if a person’s blood cells might be used to generate a specific type of macrophage cells that will remove scar tissue from the damaged liver.
What are the challenges? ▼
There are not enough suitable organ donors to match the demand of liver transplants for liver cirrhosis. Also, liver transplants require patients to take immunosuppressants to prevent transplant rejection.
Many stem cell treatments could potentially avoid the issue of immune rejection, however additional work must still be carried out to make sure that stem cell treatments, particularly pluripotent stem cell treatments, create mature and functional liver cells that are safe for transplantation in large enough quantities.
The liver is the largest internal organ of the human body. It does many jobs, including removing toxins from the blood, helping to digest food, and fighting infections. It is the only organ in the body that can regenerate itself after damage.
A piece of mouse liver containing hepatocytes and oval cells. Oval cells are thought to be the stem cells of the liver. They appear only to become active under certain circumstances, e.g. when hepatocytes cannot repair damage.
The cells that do the work in the liver are called hepatocytes. On average, each hepatocyte lives for around 200 to 300 days. In a healthy liver, hepatocytes can divide to make copies of themselves. This means they can replace the cells that die and can even repair some kinds of damage. If the liver is severely injured, another type of liver cell may come to the rescue: these cells are called hepatic progenitor cells (HPCs). HPCs are thought to be the liver’s resident stem cells and have the potential to make new hepatocytes. However, scientists are still investigating exactly what HPCs are, how they work and how we can make them produce hepatocytes more efficiently.
In chronic liver disease, a lot of liver damage happens over a long period of time. The normal repair processes are impaired and scars are formed in the liver (also called cirrhosis). The only currently available treatment for patients with cirrhosis is a liver transplantation. However, transplants are expensive, the process requires lifelong immunosuppression and there are not enough organ donors to treat all patients. Alternative therapies must therefore be found for patients with liver cirrhosis.
A piece of diseased mouse liver red staining indicates scarring
Other than a liver transplant, there are currently no conventional treatments or stem cell treatments for chronic liver disease that are approved for clinical use. However, in the long term, stem cells might provide the ability to develop new approaches for treatments:
- Preliminary clinical trials have seen some success in transplanting new hepatocytes into a patient’s liver. However, there are several large obstacles to this approach. Attachment (or engraftment) of these new cells into the liver is often very low. Also, transplanted cells are susceptible to attack / rejection by the immune system (transplant rejection). The biggest issue for this treatment is that this procedure requires large numbers of new cells for transplant, which are not readily availabile. On this last issue, stem cells, such as induced pluripotent stem cells (iPSCs), combined with new culturing techniques could offer significant help in creating enough new hepatocytes for transplants. Using iPSCs to create new hepatocytes may also help avoid attack by the immune system, since iPSCs can be made from cells taken from a patient, such as their skin cells. However, there are still a number of fundamental questions that must be answered before hepatocyte transplants using stem cells can be used clinically. For example, it will be important to find out if stem cell-derived hepatocytes are safe to treat patients and are as functional as normal hepatocytes.
- Researchers are working to identify liver stem cells more precisely and understand how they might be used to treat patients. Researchers are currently working towards establishing new techniques to identify, isolate, and expand liver stem cells from donor tissue for transplantation.
- Bio-artificial livers are an area of growing research that combine technology with biology to create a device similar to a dialysis machine that contains living hepatocytes. In theory, the cells in this device could remove toxins, produce essential proteins for the body (such as albumin for blood serum), and provide other vital roles of a healthy liver. As with hepatocyte transplant treatments, obtaining large enough numbers of human hepatocytes to live in these bio-artificial livers is a major obstacle. Researchers are attempting to address this issue by using hepatocytes from animal donors (such as pigs) or human stem cells (such as iPSCs) to grow large numbers of fully functional hepatocytes. Clinical results in studies examining bio-artificial livers have been mixed, with some showing no benefits over current treatment methods. However, next generation technologies for growing cells in these bio-artificial livers may greatly advance the quality of the cells, cell metabolic activity and overall effectiveness of these devices for treatment.
- Research is also advancing technologies to bioengineer whole organs, including the liver. Bioengineering a liver is complex, requiring the ability to assemble extremely large numbers of functional hepatocytes into specific three-dimensional structures with other types of cells, such as cells that create the vascular system. Researchers have determined how to create scaffolds for hepatocytes to grow on and direct their general arrangement, but there are still large challenges. Once again, having large numbers of human hepatocytes is a problem. In addition, it is still not clear how to incorporate a vascular system and other types of cells into these bioengineered livers. Stem cells, particularly iPSCs, offer the potential for creating the large numbers of hepatocytes needed, but researchers have to make sure that these cells have the appropriate levels of metabolic activity and will not continue to multiply once in the body. Unregulated growth in stem cell-made hepatocytes has potential to lead to tumours. Bioengineering the liver with stem cells is an ambitious goal, but has the potential to avoid or solve many problems associated with other treatment methods. Such a technology would completely replace the damaged liver with a new liver and potentially avoid attack by the immune system if made with iPSCs.
Hepatocyte-like cells grown from human embryonic stem cells
Another route to new treatments might be to use cells made from a patient’s own blood to help repair damaged liver tissue. Cells in the blood called ‘blood monocytes’ can be grown in laboratories to produce large quantities of another type of cell in the blood called macrophages. When tested in mice with damaged livers, macrophages show a beneficial role in regenerating liver tissue and removing scar tissue in the liver. When scarring is reduced, the liver is able to work better. Recent work has shown that macrophages can secrete enzymes that break down scar tissue directly, and also help remove cells that produce the scar tissue in the first place. Human macrophages are now being tested in patients with cirrhosis in clinical trials to test how safe and effective they are. Macrophages are an attractive cell therapy because they can be derived from a patient’s own blood cells and therefore would not be rejected by the immune system, as sometimes happens with organ transplants.
12 Facts About the Liver
You may not think much of your liver, hidden as it is deep inside your body, but your liver runs a whole lot of functions on your behalf to keep you healthy. Not only is it your largest internal organ, it is in charge of hundreds of different functions ranging from fighting infection, to manufacturing proteins and hormones, and helping clot your blood.
This reddish brown organ has two lobes, on the right and left, and it hangs out just on top of the gallbladder and next to parts of the pancreas and intestines. Your liver and these neighboring organs work as a team to digest and absorb your food. Its main job is to filter the blood that comes from the digestive tract, before it hits the rest of your body. The liver also detoxifies chemicals and metabolizes drugs. As it does so, the liver secretes bile that ends up back in the intestines. The liver also makes proteins important for blood plasma and other functions. With some expert support, here are 12 facts about this underappreciated, hardworking organ.
1. IT HAS A LOT OF JOBS.
The liver is a very complicated organ with a role in nearly every bodily function, according to Nancy Reau, MD, the section chief of hepatology and associate director of organ transplantation at Rush University. Some of its jobs include making and storing energy producing proteins vital for body function processing drugs—prescriptions, OTCs, and “drugs of abuse” and playing a vital role in immune function. “Although it’s hard to quantify all of the liver’s many roles, it is easy to see how sick a person becomes when the liver stops functioning,” says Reau, who is also co-chair of the American Liver Foundation’s medical advisory committee.
2. IT'S THE SECOND BIGGEST ORGAN NEXT TO SKIN.
Your liver weighs about the same as a small Chihuahua, often as much as three pounds [PDF], and is about the size of a football. It's located just beneath your rib cage on the right side of your body. If you could feel it, it would be rubbery to the touch.
3. IT HAS A DUAL IDENTITY.
Organs usually have a job specific to one region of the body. Glands are specialized types of organs that remove substances from the blood, alter or process them, then release them to other parts of the body or eliminate them. In that respect, the liver, which filters your body’s toxins (such as drugs and alcohol) and pushes them out of your body, is also a gland.
4. IT'S A BLOODY ORGAN.
At its fullest, the liver holds approximately 10 percent of the blood in your body, and pumps nearly 1.5 liters through itself per minute.
5. THE FIRST LIVER TRANSPLANT WAS NOT A GREAT SUCCESS.
Back in 1963, when Dr. Thomas E. Starzl performed the first human liver transplant at the University of Colorado Medical School, success was limited due to the wrong kinds of immunosuppressive drugs, with no patient living more than a few weeks. However, only four years later, the expansion of available immunosuppressive drugs made the first successful liver transplant possible.
6. IT'S THE ONLY ORGAN THAT CAN COMPLETELY REGENERATE.
Like Wolverine, the liver has the incredible ability to completely regrow, and it only needs as little as 25 percent of the original tissue to do so. “When a person donates more than half of their liver to someone who needs a transplant, the liver returns to its original size in nearly two weeks,” Reau tells Mental Floss. According to a 2009 study in the Journal of Cell Physiology, evolutionary safeguards are responsible for this regenerative effect due to the numerous functions performed by the liver. “This process allows liver to recover lost mass without jeopardizing viability of the entire organism,” the authors write.
7. GOOD THING, BECAUSE YOUR BRAIN DEPENDS ON A HEALTHY LIVER.
The liver is a major regulator of plasma glucose and ammonia levels. If these get out of control they can contribute to a condition known as hepatic encephalopathy, and eventually coma. In other words, if you want your brain to function, you need a working liver.
8. LIVER CONDITIONS MAY BE SYMPTOMLESS.
Liver conditions are among those that pose a quandary for diagnosis. Because many liver conditions from hepatitis to cirrhosis may have no symptoms in the early stages. “You can even have a serious liver injury when your liver tests are all normal,” says Reau.
9. BEWARE YOUR NATURAL SUPPLEMENTS, TOO.
You may think if an herb or supplement has the word natural on the bottle that it’s safe. However, Reau cautions, “Herbs and all-natural therapy [are] processed by the liver in the same way that FDA-approved medications are processed.” It’s best to talk with your doctor if you’re uncertain. Although liver injury is uncommon for both prescribed and complementary therapies, being “all natural” does not eliminate all risk.
10. YOUR LIVER IS CONCERNED ABOUT YOUR WEIGHT …
Your body needs about one gram (.03 ounces) of liver for every kilogram (35 ounces) of your body weight in order to effectively do its job, Dr. Neil Mukherjee, a liver surgeon and fellow at Florida Hospital's Southeastern Center for Digestive Disorders & Pancreatic Cancer, tells Mental Floss.
11. … AND IT RAISES YOUR BILE.
The liver is a busy brew factory of bile, that yellow, green or brownish fluid you only ever see when you’re greeting the toilet with the stomach flu or a hangover. It produces about 700 to 1000 ml of the stuff every day. The bile gathers in little ducts and then moves on to the main bile duct, where it’s carried to the duodenum of the small intestine, either directly or via the gallbladder. While it may sound gross, bile is key to your body's ability to break down and absorb fats.
12. NO MATTER SHAPE OR SIZE, ALL VERTEBRATES HAVE ONE.
Every vertebrate—that is, any living being that has a spinal cord—has a liver, a necessary part of survival. And, these livers all have a similar structure, performing the same essential tasks in all these bodies.
Split into two sections, the right and left lobes, the liver’s main function is to filter the blood that comes from your digestive tract before passing it along to the rest of your body. It is responsible for more than 500 important functions that include:
- Helping your blood clot
- Breaking down alcohol, chemicals, and other drugs
- Making glucose, a sugar that your body can use for a quick burst of energy
At any given time your liver contains about 10 percent of your body’s total blood volume, and it filters 1.4 liters of blood per minute.
So, what does the liver do? Your liver is your only organ that can regenerate, or regrow, itself. The human liver has the greatest regenerative capacity of any of the organs within the body. As a result, you can donate part of your liver to someone else, and have both your liver and the recipient’s liver grow to near full size again, regaining its function.
TGF㬡: An Essential Regenerative Cytokine or a Regeneration Terminator?
Few cytokines have elicited as much interest and contradiction in liver growth biology as TGF㬡. It is produced predominantly by stellate cells (Ikeda et al., 1998), but most cells in all tissues have been shown to produce TGF㬡 at some point in their life cycle. It is not clear whether hepatocytes actually produce TGF㬡, though it is produced by most carcinomas derived from hepatocytes or hepatoblasts (Luo et al., 2006). TGF㬡 is mito-inhibitory for most epithelial cells and it is produced by mesenchymal cells in most tissues. It stimulates synthesis of multiple extracellular matrix proteins from mesenchymal cells (Roberts et al., 1992). It inhibits proliferation of hepatocytes in culture (Houck and Michalopoulos, 1989), suppresses production of HGF (Gohda et al., 1992) and suppresses expression of urokinase and activation of HGF (Mars et al., 1996). When administered in high doses, TGF㬡 delays or partially suppresses the peak of DNA synthesis at 24h after PHx (Russell et al., 1988). HGF and EGF, whose receptors are activated fully prior to the upregulation of TGF㬡, are known to induce synthesis of TGF㬡 in hepatic organoid cultures and may be the signals behind the TGF㬡 rise during regeneration (Michalopoulos et al., 2001). Given its mito-inhibitory properties on hepatocytes, it is enigmatic that TGF㬡 is produced at high levels during liver regeneration. New TGF㬡 synthesis starts at 2𠄳 h after PHx and it remains elevated until 72 h (Jakowlew et al., 1991). Similar to other cytokines involved in this process, TGF㬡 levels also rise in the plasma very shortly after PHx and remain elevated for several hours (Michalopoulos and DeFrances, 2005b). Hepatocytes from regenerating liver are resistant to the mito-inhibitory effects of TGF㬡, and the expression of TGF㬡 receptors I, II decreases in the first 48 h after PHx (Houck and Michalopoulos, 1989 Chari et al., 1995). Resistance to TGF㬡 might be conferred by the decrease in expression of its receptors, or by the high levels of norepinephrine (see above) or by the fact that regenerating hepatocytes produce TGFα. Whatever the mechanism, regenerating hepatocytes manage to escape the mito-inhibitory effect, leaving the question as to the function served by TGF㬡. To better understand (or, more effectively speculate) on the role of TGF㬡, we need to examine changes related to it both at the beginning and at the end of the regenerative process. Immunohistochemistry for TGF㬡 shows that the protein is gradually being removed as a wave from the periportal to the pericentral regions (Jirtle et al., 1991). This has not as yet been correlated with similar changes in TGF㬡 binding proteins, such as decorin. Of interest, behind the edge of TGF㬡 removal, there is a wave of proliferating hepatocytes in mitosis. This suggests that removal of TGF㬡 protein from the liver parenchyma (corresponding with its rise in the plasma) is a necessary step to allow hepatocytes to proliferate. The experiments with dominant negative constructs against receptors for either TGF㬡 or activin (see III above) also suggest that TGF㬡 plays an active role in normal quiescent liver in keeping hepatocytes in G0 phase, by exercising a “tonic” effect and enabling them to carry their differentiated functions (Kogure et al., 2000 Ichikawa et al., 2001). Removal and inactivation of TGF㬡 (by binding to alpha-2-macroglobulin in the plasma (LaMarre et al., 1991), and mobilization and activation of HGF (Pediaditakis et al., 2001) create an imbalance of agonists and antagonists that undoubtedly contributes to the mitogenic signaling cascade for hepatocytes.
Given its mito-inhibitory properties and its upregulated expression as regeneration advances, TGF㬡 has been thought as being the natural stimulus that terminates liver regeneration. While this hypothesis is attractive, there has not been much experimental support for it. Mice with transgenic over-expression of TGF㬡 in hepatocytes do regenerate almost normally, despite the presence of very high TGF㬡 levels in liver and plasma (Sanderson et al., 1995). Knockout mouse strains with elimination of TGF㬡 receptors have normal ending of liver regeneration, unless there is concurrent elimination of activin by administration of follistatin (Oe et al., 2004). Activin is also a mito-inhibitor for hepatocytes (Ho et al., 2004). It is possible that termination of regeneration requires the combined effect of both activin and TGF㬡.
Regardless of its potential as a regeneration terminator, TGF㬡 is thought to play an important role to play in the assembly of hepatic tissue towards the end of regeneration. TGF㬡 stimulates production of many extracellular matrix proteins in many tissues including liver. TGF㬡 also stimulates tubulogenesis and formation of neovascular structures in endothelial cells in collagen gels (Pepper et al., 1993 Holifield et al., 2004). New extracellular matrix is being synthesized at the end of regeneration, and the process of forming the new sinusoidal capillary network also occurs after 3 days post-PHx, both at a time when TGF㬡 expression is at its highest levels. TGF㬡 also rises at the end of wound healing in association with similar events (Murphy et al., 2006). It is also produced by tumors at high levels, and it is thought to be associated with production of tumor matrix by the stromal cells.
Blood Supply to the Liver
In the hepatic portal system, the liver receives a dual blood supply from the hepatic portal vein and the hepatic arteries.
Outline the blood flow to and from the liver
- The hepatic portal vein supplies 75% of the blood to the liver, while the hepatic arteries supply the remaining 25%.
- Approximately half of the liver’s oxygen demand is met by the hepatic portal vein, and half is met by the hepatic arteries.
- The hepatic portal system connects the capillaries of the gastrointestinal tract with the capillaries in the liver. Nutrient-rich blood leaves the gastrointestinal tract and is first brought to the liver for processing before being sent to the heart.
- hepatic arteries: A blood vessel that supplies oxygenated blood to the liver.
- hepatic portal vein: A vessel located in the abdominal cavity that is formed by the union of the superior mesenteric and splenic veins that channel blood from the gastrointestinal tract and spleen to the capillary beds in the liver.
- cofactors: A substance, especially a coenzyme or a metal, that must be present for an enzyme to function.
In the hepatic portal system, the liver receives a dual blood supply from the hepatic portal vein and hepatic arteries. The hepatic portal vein carries venous blood drained from the spleen, gastrointestinal tract and its associated organs it supplies approximately 75% of the liver’s blood. The hepatic arteries supply arterial blood to the liver and account for the remainder of its blood flow.
Oxygen is provided from both sources approximately half of the liver’s oxygen demand is met by the hepatic portal vein, and half is met by the hepatic arteries. Blood flows through the liver tissue and empties into the central vein of each lobule. The central veins coalesce into hepatic veins that collect the blood leaving the liver and bring it to the heart.
Hepatic veins: An image of a liver with the hepatic veins labeled. They are located in the inferior vena cava.
A portal system is a venous structure that enables blood from one set of capillary beds to drain into another set of capillary beds, without first returning this blood to the heart. The majority of capillaries in the body drain directly into the heart, so portal systems are unusual.
The hepatic portal system connects the capillaries of the gastrointestinal tract with the capillaries in the liver. Nutrient-rich blood leaves the gastrointestinal tract and is first brought to the liver for processing before being sent to the heart. Here, carbohydrates and amino acids can be stored or used to make new proteins and carbohydrates.
The liver also removes vitamins and cofactors from the blood for storage, as well as filters any toxins that may have been absorbed along with the food. When any of these stored substances are needed, the liver releases them back into circulation through the hepatic veins.
Hepatic portal circulation: A diagram that shows the hepatic portal vein and its territory.
How Your Liver Tames Toxins
After blood leaves your digestive tract and flows into your liver, the liver gears up to process a wide variety of dangerous chemicals in your bloodstream.
The cells that process these toxins break them down into molecules that are less risky for your body. For example, liver cells turn ammonia, which is released when you digest proteins, into a harmless byproduct called urea, which passes out of your system when you pee.
Your liver also safely handles the alcohol you drink by turning it into a chemical called acetate, which other tissues in your body break down into carbon dioxide and water.
What controls organ regeneration and why can't humans do it?
The liver is the only human internal organ capable of natural regeneration of lost tissue as little as 25% of a liver can regenerate into a whole liver. This is, however, not true regeneration but rather compensatory growth. The lobes that are removed do not regrow and the growth of the liver is a restoration of function, not original form. This contrasts with true regeneration where both original function and form are restored. In liver, large areas of the tissues are formed but for the formation of new cells there must be sufficient amount of material so the circulation of the blood becomes more active.
This is predominantly due to the hepatocytes re-entering the cell cycle. That is, the hepatocytes go from the quiescent G0 phase to the G1 phase and undergo mitosis. This process is activated by the p75 receptors. There is also some evidence of bipotential stem cells, called hepatic oval cells or ovalocytes (not to be confused with oval red blood cells of ovalocytosis), which are thought to reside in the canals of Hering. These cells can differentiate into either hepatocytes or cholangiocytes, the latter being the cells that line the bile ducts.
Simple animals like planarians have an enhanced capacity to regenerate because the adults retain clusters of stem cells (neoblast) within their bodies which migrate to the parts that need healing. They then divide and differentiate to grow the missing tissue and organs back. The process is more complex in vertebrates, but nevertheless, salamanders possess strong powers of regeneration, which begins immediately after amputation. Limb regeneration in the axolotl and newt has been extensively studied.
And, I know that you asked for organ regeneration, but humans are partly capable of limb regeneration as well.