Human Pancreas-on-a-Chip: A Novel Innovation for Studying Diseases

Human pancreas-on-a-chip has been developed that has enabled the elucidation of the possible causes of cystic fibrosis-related diabetes (CFRD), which is a common and often fatal complication of cystic fibrosis (CF). The chip has been developed by a team of researchers at Cincinnati Children’s Hospital Medical Center. The chip is basically a small two-chambered device, containing bioengineered human pancreatic organoids, which allows scientists to closely study the mechanisms involved in the pathogenesis of CF. The chip can also be used to study the causes of diseases such as Type 1 and Type 2 diabetes, which are not related to CF. The research findings have been published in the journal Nature Communications.

The study was led by Dr. Anjaparavanda P. Naren, Ph.D., who is the Thomas Boat Chair in Cystic Fibrosis Research and Director of the Cystic Fibrosis Research Center in the Division of Pulmonary Medicine, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA.

The co-corresponding author and study collaborator was Dr. Jaimie D. Nathan, MD, who is the Surgical Director of the Pancreas Care Center at Cincinnati Children’s Hospital and an Associate Professor of Pediatric Surgery in the Department of Surgery at the University of Cincinnati’s College of Medicine, Cincinnati, Ohio, USA.

The first author of the paper was Dr. Kyu-Shik Mun, Ph.D., who is a Research Associate in the Division of Pulmonary Medicine at Cincinnati Children’s Hospital.

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Cystic Fibrosis & its Complications

Cystic fibrosis is a genetic lung disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene encodes the CFTR protein, which is a membrane protein and chloride channel. The mutation causes disturbances in water and salt balance in the body, leading to a build-up of thick, sticky mucus in the lungs and airways. This results in breathing problems, pneumonia, sinusitis, and other complications.

One of the most common complications of CF is CFRD, which affects 20 percent of adolescents and 40-50 percent of adults suffering from CF. Although CFRD is somewhat similar to Type 1 and Type 2 diabetes, it is a clinically distinct condition. It is primarily caused by insulin insufficiency arising from the destruction of the pancreatic islets of Langerhans. CFRD is associated with worsening of lung function, reduced nutritional status, and a propensity for chest infections.

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Challenges in Studying Cystic Fibrosis-Related Diabetes (CFRD)

The chances of developing CFRD progressively increases as patients with CF get older. Until the development of the pancreas-on-a-chip, there was no effective method to study CFRD in the lab to find effective treatments for the condition.

“Mouse models of CF don’t faithfully recreate CFRD in the lab, and it wasn’t possible to study the disease at the depth we achieved in this study,” said Naren. “Our technology closely resembles the human pancreas and potentially may help us find therapeutic measures to manage glucose imbalance in people with CF, which is linked to increased illness and death.”

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How was the Pancreas-on-a-Chip Developed?

The following steps were involved in developing the pancreas-on-a-chip device:

• The islets of Langerhans and ductal epithelial cells were isolated from pancreatic tissue samples from patients undergoing surgery
• A microfluidic device was used for culturing the pancreatic ductal cells
• The microfluidic device consisted of transparent dual-chambers, one on top of the other, containing biochemical solutions having specific compositions
• The chambers were separated by a thin porous membrane that allowed interactions to take place between the two chambers
• Ductal epithelial cells were cultured in the top chamber, and the islets of Langerhans were cultured in the bottom chamber
• The cells grew into three-dimensional (3D) pancreatic organoids that exhibited cell-to-cell interactions, fluid exchange, and other properties, resembling the natural human pancreas

How was the Pancreas-on-a-Chip Tested?

The pancreas-on-a-chip was tested by evaluating whether it could recreate CFRD in vitro:

• The CFTR gene expression was disrupted in the organoids present within the chip
• This impaired cell-to-cell interactions, fluid exchange, and endocrine functions
• This led to insulin deficiency, thereby mimicking CFRD, similar to that observed in the natural human pancreas
• This confirmed that the CFTR gene played a direct role in inhibiting insulin secretion, leading to the development of CFRD in CF patients

What are the Applications of Pancreas-on-a-Chip Technology?

Some of the potential applications of the in vitro chip technology include the following:

• Study of CFRD and glucose imbalance in specific patient populations
• Personalized diagnosis of different disease conditions
• Assay of variability in glucose levels in different individuals
• Correlation of glucose levels with the type of CFTR gene mutation
• Evaluation of potential drug molecules against CFRD

Future Plans

The research team plans to use the pancreas-on-a-chip in a pilot study to test the effect of FDA-approved drugs on CFTR gene expression. This will enable the researchers to determine whether drug-mediated modulation of the CFTR gene would be able to slow-down, stop, or even reverse CFRD in an in vitro simulation of the condition.

Funding Source

The study was funded by the National Institutes of Health and the Cystic Fibrosis Foundation, USA.

Reference:

1. Human Pancreas on a Chip Opens New Possibilities for Studying Disease - (https://www.cincinnatichildrens.org/news/release/2019/pancreas-chip)

Source-Medindia