Key Results from Study
This is the first human-based, multi-chamber system that models a NAFLD phenotype with adipocytes and demonstrates the importance of the interaction between these two different organ tissues in the disease.
- The microfluidic system, composed of hepatocytes and adipocytes in serum-free medium, replicates aspects of the NAFLD phenotype
- Data highlights the need to include adipose tissue in preclinical NAFLD models
ORLANDO, Fla.--(BUSINESS WIRE)-- Hesperos Inc., pioneers of Human-on-a-Chip® in vitro systems, today announced the publication of a peer-reviewed article demonstrating that a Human-on-a-Chip® (HoaC) cell-based, dual-chamber system comprising functional liver cells and adipose tissue could be used to model important metabolic characteristics linked to nonalcoholic fatty liver disease (NAFLD). The manuscript, titled “Validation of an adipose-liver human-on-a-chip model of NAFLD for preclinical therapeutic efficacy evaluation,” was published in Scientific Reports.
NAFLD is the most common form of liver disease and affects around 24% of individuals worldwide. The disease is characterized by an excess of fat stored in liver cells in people who drink little to no alcohol. While earlier stages of NAFLD usually cause no symptoms, some patients may experience more serious complications due to continuous liver inflammation. This can lead to a severe form of fatty liver disease known as nonalcoholic steatohepatitis (NASH), which may progress to liver scarring (cirrhosis), end-stage liver failure and hepatocellular carcinoma. Conditions including obesity and Type 2 diabetes can increase a patient’s risk for developing NAFLD and NASH.
Previous reports demonstrate the successful treatment of NAFLD in cell and rodent models; however, these therapies translate poorly in human clinical trials. Therefore, there is a crucial need for novel platforms that more accurately recapitulate the features of NAFLD.
In the Scientific Reports article, researchers from the NanoScience Technology Center at the University of Central Florida (UCF) and Hesperos describe a microfluidic HoaC model containing human-derived hepatocytes and adipocytes in a recirculating serum-free medium. Initially, cell functionality of the hepatocytes and adipocytes in monoculture were characterized using media combinations designed to simulate different clinical conditions. To create the NAFLD HoaC model, the hepatocytes and adipocytes were housed in an interconnected, two-chamber microfluidic system which enabled cross-communication between the two organ tissues.
“To our knowledge, this is the first human-based, multi-chamber system that models a NAFLD phenotype with adipocytes and demonstrates the importance of the interaction between these two different organ tissues in the disease,” said James J. Hickman, Ph.D., Chief Scientist at Hesperos and Professor at the University of Central Florida. “This interconnected, human-based, multi-organ platform enables different cells to communicate with each other through the recirculating medium and can be an important tool to understand the disconnect between preclinical data and human clinical results.”
Results indicated that the presence of TNF-α proinflammatory medium did not cause hepatocyte steatosis in monoculture, however steatosis was significantly increased following co-culture with adipocytes in the two-chamber system. Previous reports have shown that the proinflammatory molecule TNF-α is secreted by macrophages that infiltrate adipose tissue. Additionally, decreased CYP3A4 activity in hepatocytes was shown following exposure to proinflammatory medium in the system, consistent with the lowered expression of CYP3A4 mRNA in NASH patients and decreased enzymatic activity in NAFLD in vitro models. Finally, adipocytes showed changes in adipokine secretion when exposed to proinflammatory medium in the two-chamber system, consistent with previously reported obesity and NAFLD studies. Taken together, these results show how this HoaC model accurately replicates important pathological features of NAFLD.
The insulin-sensitizing drug metformin was also evaluated in the HoaC NAFLD model. Supported by studies from preclinical animal models and in vitro model systems, metformin has been previously proposed as a treatment for diabetes and NASH. However, the therapy has not shown clinical benefit in humans. Data from the two-chamber HoaC system showed that metformin significantly decreased steatosis but only at higher physiological doses not typically used in humans. These discrepancies highlight the need for better preclinical models that recapitulate the mechanisms of NAFLD to evaluate drug efficacy.
Funding for this research was provided by the National Institute on Aging at the National Institutes of Health through a grant evaluating disease comorbidities and a grant from the National Center for Advancing Translational Sciences.