Cascia

Liver

 

Stem cell therapy has show promise in liver regeneration applications.  While the liver, unlike other ograns, has the ability to regenerate naturally, when disease is present its natural mechanisms may not be sufficient.  There are two indications in particular where stem cells may be extremely beneficial:


 

Acute Liver Failure

Acute liver failure, also known as fulminant hepatic failure, is a rare and serious condition where the liver suddenly stops working. The underlying cause of acute failure varies but the two most common auses are toxicity, such as acetaminophen overdose or exposure to environmental toxins such as heavy metals, and progression of chronic liver disease such as hepatitis. The term acute-on-chronic liver failure (ACLF) has been used to define a syndrome in patients with acutely decompensated cirrhosis and association with an intense systemic inflammatory response. The most common precipitating conditions are infections, alcoholic hepatitis, and other organ failures.The 28‑day mortality rate for ACLF is estimated to be 26% overall, with higher rates for the more severe forms

Liver failure, regardless of the cause, is a severe medical condition requiring immediate treatment.  The liver interacts with other organs and failure is often accompanied by severely reduced kidney function, encephalopathy (swelling of the brain due to accumulation of toxins that affect the brain, such as ammonia), and coagulation failure.

Liver Fibrosis

A common manifestation of any chronic liver disease is the replacement of normal functional tissue with scar.  As collagen Type IV, the normal type found in the liver, is replaced by high‑tensile strength collagen Type I, the type found in scar tissue, the liver becomes less flexible, function declines, and with advanced pathology the liver become cirrhotic. The liver interacts with other organs and failure is often accompanied by severely reduced kidney function, encephalopathy (swelling of the brain due to accumulation of toxins that affect the brain, such as ammonia), and coagulation failure. A common manifestation of any chronic liver disease is the replacement of normal functional tissue with scar.  As collagen Type IV, the normal type found in the liver, is replaby high‑tensile strength collagen Type I, the type found in scar tissue, the liver becomes less flexible, function declines, and with advanced pathology the liver become cirrhotic.  

There is a rapidly growing incidence of MAFLD (metabolic dysfunction-associated fatty liver disease) and its associated condition MASH (metabolic dysfunction-associated steatohepatitis).  Fatty liver disease is the buildup of small fat particles in the liver, largely as a result of poor dietary habits, lack of exercise and other lifestyle issues.

The precise incidence of fatty liver disease is difficult to establish because there are no obvious symptoms until the condition progresses.  A definitive diagnosis can only be made with a histological analysis of their liver tissue following a biopsy, or magnetic resonance imaging of their abdomen.  Neither are routine diagnostic procedures performed in the absence of other symptoms.

As the chart at left shows, there is clearly a genetic component as well since more than half of adults of Hispanic ethnicity have fatty liver disease compared with about a third of African Americans.

MAFLD is often a progressive disease, with about half of the patients progressing to MASH over a seven-year period.  MASH is quite similar except that enough liver tissue has become scarred at that point that a physician can feel the difference in elasticity when making a manual examination of the abdomen, and there may be changes in liver enzyme levels.

If MASH is not treated, an estimated 1 in 4 patients will progress to more serious fibrosis, cirrhosis, or hepatocellular carcinoma.


Stem Cell Therapy

The liver exhibits a tremendous ability to regenerate itself to an extent not found elsewhere in the human body, but when a progressive disease becomes too advanced this capability is not sufficient to maintain liver health.  A liver transplant is often the recommended solution, but there is a chronic shortage of transplant organs with an estimated 1,400 patients eligible for transplant dieing before an organ becomes available, and there are additional patients who are not eligible due to age, overall physical condition, or presence of disqualifying factor such as active infectious disease.

Success of stem cell treatment is generally measured by the patient’s MELD score (model for end stage liver disease), and their blood chemistry values, especially albumin.  Several investigators have administered mesenchymal stem cells to patients with acute liver failure with reports of promising results, albeit on a limited number of patients, with decreased MELD scores and improved blood chemistry.  Stem cell treatments hold the promise to obviate the need for a liver transplant in some cases, and to increase the amount of time the patient can survive while waiting for a transplant organ to become available.  The MELD score is frequently used by transplant teams to estimate the risk of death without a transplant, so a decreased MELD score is an indicator of increased survival. 

The image at the right shows stains of liver sections from a mouse model treated with stem cells with the upper panel showing substantial invasion of scar tissue versus the bottom panel showing that collagen deposition was significantly reduced. Stem cells treatments have likewise proven effective in reversing fibrosis in animal models.  In one study a group with diabetes‑associated fatty liver disease was fed a high‑fat diet, following which a course of stem cells was administered.  It was demonstrated that calcium levels improved in the fatty liver cells, and their energy level was improved due to mitochondria transferring from the mesenchymal cells.  Mitochondrial transfer is a common effect seen when diseased tissues encounter healthy stem cells.  In a second study, cells were administered together with simvastatin, a commonly used statin drug.   The combination cell and drug treatment decreased hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment, and protected against hepatic fibrosis by suppressing TGF-b/Smad signaling.