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.
‘Human pancreas-on-a-chip is a new innovation that uses a microfluidic device to culture pancreatic cells to produce organoids resembling the natural pancreas. It can be used to study diseases such as cystic fibrosis (CF) and cystic fibrosis-related diabetes (CFRD).’
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.
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.
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." 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 : - Human Pancreas on a Chip Opens New Possibilities for Studying Disease - (https://www.cincinnatichildrens.org/news/release/2019/pancreas-chip)
Source: Medindia
