Pancreas-on-a-chip Expected to Shed Light, Help Find New Treatments for CF-related Diabetes

Scientists have created a miniature human pancreas-on-a-chip that may help identify the cause of cystic fibrosis-related diabetes (CFRD), a common and life-threatening complication of cystic fibrosis (CF).

Researchers believe the pancreas-on-a-chip will provide insightful information about the biology of CFRD, offering a reliable way to monitor pancreatic cell responses and test potential treatments in vitro (in the lab).

The findings were reported in the study “Patient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders,” published in the journal Nature Communications.

As people with CF age, they are at greater risk that the disease’s characteristic sticky, thick mucus may damage the pancreas. If this injury is too extensive, the pancreas stops making enough insulin, much like in type 1 diabetes.

Moreover, people with CF can be insulin resistant, which means their cells do not respond normally to insulin, resembling type 2 diabetes.

Up to now, scientists have lacked an effective way to study CFRD in the lab, both to understand better how the disease unravels, and to look for potential treatments.

But now, researchers from the Cincinnati Children’s Hospital Medical Center, found an alternative that could fill this need.

“Mouse models of CF don’t faithfully recreate CF-related diabetes in the lab, and it wasn’t possible to study the disease at the depth we achieved in this study,” Anjaparavanda Naren, PhD, director of the Cystic Fibrosis Research Center and the study’s principal investigator, said in a press release.

Researchers recreated a human pancreas on small microfluidic chips harboring pancreas organoids — small, three-dimensional tissue cultures —  derived from patient cells.

Microfluidic devices are not new, but recent innovations, especially the emergence of organoids, enabled scientists to mimic the function of natural organs in vitro (in artificial cultures in the lab), which are called “organs-on-chips.”

These models offer a potential alternative to traditional animal testing, which often fails to mimic human biology and implies the sacrifice of living beings.

To create their chip, researchers used pancreatic ductal epithelial cells (PDECs, one of the most abundant cell types in the pancreas), and pancreatic islets (the cells responsible for producing insulin) donated by surgical patients.

The cells were placed in a microfluidic device made of two chambers and containing specific substances to support the cells’ survival and growth. Ductal epithelial cells were cultured in the top chamber and pancreatic islet cells were cultured in the bottom chamber, separated by a thin and porous layer that allowed communication between the two.

Within the pancreas-on-a-chip, cells grew into three-dimensional mini-organs that closely mimicked important biological features of the human pancreas, including cell-to-cell communications and fluid exchange.

Researchers then genetically engineered cells from the pancreas-on-a-chip to disrupt the CFTR gene (CF transmembrane conductance regulator, the faulty gene in CF). This impaired cell-to-cell communication, resulted in problems in fluid exchange and hormone release, ultimately leading to insulin deficiency, similar to what happens in the pancreas of a person with CF.

According to the researchers, this result confirmed that the CFTR gene has a direct role in regulating insulin secretion, and causing diabetes in CF patients.

“This uniquely developed pancreatic function monitoring tool will help to study CF-related disorders in vitro, as a system to monitor cell-cell functional interaction of PDECs and pancreatic islets, characterize appropriate therapeutic measures, and further our understanding of pancreatic function,” the researchers wrote.

“Our technology closely resembles the human pancreas and potentially may help us find therapeutic measures to manage glucose [sugar] imbalance in people with CF, which is linked to increased illness and death,” Naren concluded.

The team’s next steps will be to use the device in a pilot study to test FDA-approved therapies that modulate CFTR gene activity to see how well these treatments can slow or rescue lab-simulated CFRD.

This work was funded by the National Institutes of Health and the Cystic Fibrosis Foundation.