Scientists target human stomach cells for diabetes therapy

Stem cells from the human stomach can be converted into insulin-secreting cells in response to increased blood sugar levels, offering a promising approach to treating diabetes, according to a preclinical study from researchers at Weill Cornell Medicine.

In the study, which appeared April 27 in Natural Cell Biology, the researchers demonstrated that they could take stem cells obtained from human stomach tissue and reprogram them directly—with very high efficiency—into cells that closely resemble pancreatic insulin-producing cells known as beta cells. Transplanting small clusters of these cells reversed signs of the disease in a mouse model of diabetes.

“This is a proof-of-concept study that gives us a solid foundation for developing treatments, based on the patient’s own cells, for severe type 1 and type 2 diabetes,” said study senior author Dr. Joe Zhou, a professor. regenerative medicine and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine.

Insulin is a hormone that regulates blood glucose levels—without it, blood glucose becomes too high, leading to diabetes and its various complications. An estimated 1.6 million Americans have type 1 diabetes, which results from an autoimmune attack that destroys beta cells in the pancreas. At least several million other Americans are deficient in beta cells due to severe type 2 diabetes. Current treatment in such cases includes manual insulin injection and wearable pumps, which have many drawbacks including pain, potentially inefficient glucose control, and the need to wear complex equipment.

Biomedical researchers aim to replace beta cell function in a more natural way, with human cell transplants that work much like beta cells: automatically sensing blood sugar levels and secreting insulin as needed. Ideally, such a transplant would use the patient’s own cells, to avoid the problem of transplant rejection.

Dr. Zhou has been working towards this goal for more than 15 years. In his early experiments as a postdoctoral researcher, he discovered that ordinary pancreatic cells could be converted into insulin-producing beta-like cells by forcing the activation of three transcription factors—or proteins that control gene expression—resulting in the activation of subsequent genes necessary for normal beta cell development. In a 2016 study, again in mice, he and his team showed that certain stem cells in the stomach, called gastric stem cells, were also highly sensitive to this three-factor activation method.

“Stomach makes its own hormone-producing cells, and gastric and pancreatic cells are close together in the embryonic stage of development, so it is not too surprising that gastric stem cells can be easily converted into beta-like insulin. -secreting cells,” said Dr. Zhou.

Attempts to reproduce these results using human gastric stem cells, which can be removed from patients with relative ease in an outpatient procedure called an endoscopy, have been slowed by various technical hurdles. However, in the new study, led by first author Dr. Xiaofeng Huang, an instructor in molecular biology in medicine at Weill Cornell Medicine, the researchers finally got their way.

After converting human gastric stem cells into beta-like cells, the team grew the cells in small clusters called organoids and found that these organ-like tissue pieces rapidly became sensitive to glucose, responding by secreting insulin. When transplanted into diabetic mice, the beta-like organoids functioned in much the same way as true pancreatic beta cells, secreting insulin in response to rising blood glucose, and thereby keeping blood glucose levels stable. The transplants also continued to work for as long as the researchers monitored them — six months — showing good survival.

Dr. Zhou said that he and his lab still need to optimize their method in various ways before it can be considered for clinical use. Improvements needed include methods to scale-up production of beta cells for transplantation into humans, and modification of beta-like cells to make them less susceptible to the kind of immune attack that initially wipes out beta cells in type 1 diabetes patients.

Ultimately, the researchers hope to develop a technique that will allow relatively easy harvesting of gastric stem cells from patients, followed by transplanting, a few weeks later, insulin-producing organoids that regulate blood sugar levels without the need for further treatment.