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Scientists have created a human pancreas on a chip that has allowed them to identify the possible cause of a frequent and life-threatening complication of cystic fibrosis (CF) called diabetes badociated with CF, or CFRD.
It may also be feasible to use the small two-chamber device, composed of bio-modified pancreatic organoids, to study the causes of non-CF related conditions, such as type 1 or type 2 diabetes, according to researchers from Cincinnati Children's Hospital Medical Center. report results in Nature Communications.
However, scientists first want to know if their device can help people with cystic fibrosis – a genetic lung disease caused by a mutation in the CFTR gene. The mutation causes a water and salt imbalance on cell surfaces that clogs the lungs with thick mucus.
According to Anjaparavanda Naren, Ph.D., principal investigator of the study and director of the Cystic Fibrosis Research Center (Division of Pulmonary Medicine), CF people are aging and becoming more at risk for CFRD. Worse, until now, there was no effective way to study CFRD in the laboratory to look for better treatments.
"The mouse models of CF do not faithfully recreate CF-related diabetes in the laboratory, and it has not been possible to study the disease at the depth we reached in this study," he said. Naren. "Our technology is very similar to the human pancreas and could help us find therapeutic measures to manage the glycemic imbalance in people with CF, which is badociated with an increase in the number of illnesses and deaths."
In vitro flea technology can be used to study CFRD and glucose imbalance in specific individuals with the disease, which can be used to diagnose different manifestations of the disease in a highly personalized way. The chip can help badyze the variability of glucose measurements of different people, determine the correlation between glucose levels and the type of CFTR mutation and test small molecule interventions.
Chipping Away at the CFTR Enigma
Although it is known that mutations of the CFTR gene are at the origin of cystic fibrosis, its role in the DRFC is not clear. To answer this question, researchers began by isolating pancreatic ductal epithelial cells and pancreatic islets donated by operated patients.
The ductal organelles were grown in a transparent double chamber called a microfluidic device, which contained specific biochemical solutions to generate the pancreas on a chip. The ductal epithelial cells were cultured in the upper chamber and the pancreatic islet cells in the lower chamber, separated by a thin layer of porous membrane allowing the different chambers to interact.
The cells grew and expanded in three-dimensional pancreatic organs that mimicked cell-to-cell communication and fluid exchange, similar to the function of a naturally-grown human pancreas.
When the researchers tested the pancreas on a chip by disrupting the expression of the CFTR gene, they impaired cell-to-cell communication, fluid exchange, and endocrine function. This caused insulin deficiency and recreated the process of CFRD disease similar to that seen in a person's pancreas. The researchers confirmed that the CFTR gene plays a direct role in the regulation of insulin secretion and the cause of diabetes in people with CF.
Microfluidic devices have existed since 1979. But innovations in design and functionality, especially since the advent of organoid technology, now allow researchers to engineer biological tissue of human organs and reproduce the functioning of organs. natural in the laboratory.
Next steps
The research team, which includes the first author of the study and research badociate, Kyu Shik Mun, PhD, will now use the devices as part of a pilot study to test FDA-approved drugs that modulate the expression of the CFTR gene. The goal will be to determine the extent to which different CFTR drugs can slow down or reverse the simulated CFRD in the laboratory.
Jamie Nathan, MD, surgical director of the Cincinnati Children's Pancreas Care Center, also collaborated.
Funding for this study was provided in part by the National Institutes of Health (DK080834, DK093045, P30DK117467) and the Cystic Fibrosis Foundation (MUN18F0, NAREN14XX0).
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