The liver is one of the more complex organs in the human body, and performs many essential functions, including digestion and drug metabolism. In addition to being complex, the liver is also extremely adaptable and can regenerate itself if damaged. Hepatocytes account for about 60% of the cells within the liver, and are responsible for most of its metabolic activity, detoxification, protein secretion and bile production. When a drug enters the body, it is quickly absorbed into the bloodstream and transported to the liver. The liver then metabolizes the drug, which reduces its concentration in the bloodstream and makes it less likely to cause side effects. Because the liver is the first organ to interact with drugs (the so-called “first pass”), it is crucial to monitor the effects that these drugs have on hepatocytes during drug screening.

Unfortunately, many drugs are withdrawn from the market because they are found to cause drug-induced liver injury (DILI). Part of the reason for this is that the prevailing methods of drug toxicity testing, which use animal models, are not always accurate in their prediction of human response. Furthermore, these tests are expensive and time-consuming.

Scientists and researchers have identified cell-based assays as a faster and more cost-effective means of assessing hepatotoxicity. However, this method currently faces a number of obstacles:

Lack of standardization. Harvested hepatocytes can vary significantly depending on the human donor from which they’re harvested. This makes it difficult to assess and compare assays, even in a tightly regulated and controlled environment.

Instability (and lack of availability). Human primary hepatocytes are not as easily renewable as those harvested from animals; they also quickly lose their functional phenotype during in vitro culture.

Immaturity. As is the case with many iPSC-derived cells, iPSC-derived hepatocytes fail to achieve an adult phenotype when cultured in vitro, making them less reliable as a means of toxicity predictiveness.

Another potential method for measuring drug toxicity in the liver involves the use of hepatic organoids. This method is not without its drawbacks either, though. Specifically, the nutrients within these organoids may not diffuse fully to the center of the sphere, which can lead to a necrotic core; this necrosis may not be detected until after it has been assayed. As a result, uniformity of high-throughput organoids is extremely difficult to establish.

Working toward a solution

The team at StemBioSys hypothesizes that the challenges related to hepatic cultures may be due to the fact that existing models do not do an adequate job of recreating the cells’ native niche. This extracellular matrix (ECM) is the environment that surrounds and supports the cells, and is a critical component of cell behavior. Previously, StemBioSys has successfully developed a process of manufacturing in vitro, cell-derived ECMs on a larger scale. The team now aims to use this same technology to develop a tissue-specific niche for the culture of iPSC-derived hepatocytes.

The work that StemBioSys proposes serves to achieve four specific goals:

1. Produce and characterize a tissue-specific ECM (HepatoMatrix) from hepatic cells.
   

2. Test the HepatoMatrix for efficacy and cell maturity, as compared to traditional methods of culturing maturing iPSC-derived hepatocytes.
   

3. Evaluate the relative efficacy of the HepatoMatrix in drug toxicity testing.
   

4. Determine the consistency and scalability of the HepatoMatrix product.

The bigger picture

Through this ongoing work, the team aims to develop an effective and scalable product for use in hepatotoxicity testing. If it is successful, HepatoMatrix could provide many benefits:

Advancements in toxicology studies. By offering a method of more accurately predicting toxicity in certain medications, HepatoMatrix can remove many of the roadblocks currently facing providing scientists, researchers and drug companies - and open the door to further advancements in drug research.

Cost and time savings. Animal testing is expensive and slow. In vitro cell-based assays are less expensive and require much less time; they can predict toxicity earlier in the testing process. (As an aside, cell-based assays are also unburdened by the ethical concerns that have been raised regarding animal testing.)

Flexibility. Hepatocytes can be used for more than just toxicity testing. From genetic studies to disease modeling, there are many different ways in which a stable source of renewable hepatocytes can be used for further scientific studies.

With the proposed HepatoMatrix project, StemBioSys aims to minimize the obstacles that currently exist in hepatotoxicity testing, and to offer innovative new ways of using iPSC-derived hepatocytes in clinical research.

Located in San Antonio, TX, StemBioSys develops cell culture technologies licensed from The University of Texas Health Science Center, San Antonio. Our work represents the next evolution in stem cell research. For more information about StemBioSys and our patented technology, please contact us.