The key to a new cellular therapy for diabetes may lie in the stomach, according to the results of a new study; researchers have used stomach cells to create "mini-organs" that produce insulin when transplanted in mice.
In the US, around 29.1 million people have diabetes. Of these, around 1.25 million have type 1 diabetes, where the destruction of beta cells in the pancreas halts insulin production, leading to inadequate regulation of blood glucose levels.
In an attempt to find a cure for the condition, researchers have spent years searching for ways to replace these insulin-producing beta cells.
Last October, for example, Medical News Today reported on a study in which researchers reprogrammed pancreatic duct-derived cells (HDDCs) to behave like beta cells and produce and secrete insulin.
But this latest study - published in the journal Cell Stem Cell - suggests that cells from the lower section of the stomach, known as the pylorus region, show the greatest potential to be reprogrammed to act like beta cells.
Reprogrammed stomach cells normalized glucose levels in mice
Senior study author Qiao Zhou, of the Department of Stem Cell and Regenerative Biology at Harvard University in Boston, MA, and colleagues genetically engineered mice to express three genes that have the ability to convert cells into beta cells.
This enabled the team to pinpoint which cells in the mice were most likely to have insulin-producing potential.
- Of the 29.1 million people believed to have diabetes in the US, around 8.1 million are undiagnosed
- Around 1.4 million Americans are diagnosed with diabetes every year
- Type 2 diabetes is the most common form, accounting for around 90-95% of all cases.
"We looked all over, from the nose to the tail of the mouse," says Zhou. "We discovered, surprisingly, that some of the cells in the pylorus region of the stomach are most amenable to conversion to beta cells. This tissue appears to be the best starting material."
The pylorus region is the area that joins the stomach to the small intestine.
The researchers explain that when they reprogrammed various cells to behave like beta cells, the pylorus cells had the strongest response to high blood glucose levels in the mice, producing insulin in order to bring their glucose levels back to normal.
To test the effectiveness of these cells, the researchers destroyed the beta cells of two groups of diabetes mouse models. One group had their pylorus cells reprogrammed to act like beta cells, while a control group did not undergo pylorus cell reprogramming.
While the mice in the control group died within 8 weeks, those that had their pylorus cells reprogrammed maintained their insulin and glucose levels for the entire monitoring period, which was up to 6 months. This suggests that the reprogrammed pylorus cells compensated for the lack of beta cells.
Asked why pylorus cells appear to be the best cells to convert for insulin production, Zhou told MNT: "From our molecular and physiological studies, pylorus derived beta-cells appear to most closely resemble native beta cells in the pancreas and therefore can do a better job at regulating blood glucose."
The team notes that there is another benefit to using cells from the pylorus region: stem cells in this area renew themselves regularly. They explain that when the first set of reprogrammed cells were destroyed in the mice, pylorus stem cells regenerated them.
"In various disease states, you have a constant loss of beta cells," says Zhou. "We provide, in principle, an advantage to replenish those."
Mini-stomachs compensated for lack of beta cells
Zhou explains that in the study, mice were engineered to express three genes that have the ability to reprogram cells to beta cells, but this technique would not be feasible in humans.
In order to address this problem and pave the way for a potential clinical therapy, the researchers extracted some stomach tissue from mice and engineered the tissue cells in a lab to express factors that would lead to the conversion of stomach cells to beta cells.
Next, the team coaxed the reprogrammed cells to form a mini-stomach measuring around 0.5-1 cm in diameter, before transplanting these tiny organs in the membranes of the abdominal cavities of the mice.
The researchers then destroyed the beta cells of the mice in order to see whether the mini-stomach would take over their job.
They found that for five of the 22 mice who were transplanted with the mini-stomachs, their blood glucose levels remained normal. The team says this is the success rate they expected to see.
"When you put this together, you are basically asking the harvested stem cells to self-organize into an organ on a matrix," explains Zhou. "The limitation is all about whether the tissue you transplanted can successfully reorganize with the right layers."
Mini-stomachs: a feasible treatment for diabetes patients?
While there is a long way to go before mini-stomach transplantation becomes an option for diabetes patients, Zhou believes their study suggests it is feasible:
"What is potentially really great about this approach is that one can biopsy from an individual person, grow the cells in vitro and reprogram them to beta cells, and then transplant them to create a patient-specific therapy. That's what we're working on now. We're very excited."
In fact, Zhou told MNT that the team has already developed human mini-stomachs that can produce insulin. "We are now testing them in mouse models," he said. "Our aim is to generate patient-specific beta-cells from these samples and transplant them back."
But will these mini-stomachs ever yield a cure for diabetes? "I think our method paves the way for a new approach of cellular therapy to treat diabetes for sure," Zhou told us. "A cure for diabetes will require a more multi-pronged approach. No single treatment, in my opinion, can completely cure diabetes."
Last month, MNT reported on the development of a promising treatment strategy for patients with type 1 diabetes in the form of encapsulated pancreas cells.