Scientists target human stomach cells for diabetes therapy

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In the study, which appeared April 27 in nature Cell Biology, The researchers showed that they could take stem cells obtained from human stomach tissue and reprogram them directly, with surprisingly high efficiency, into cells that closely resemble insulin-secreting pancreatic cells known as beta cells. Transplantations of small groups of these cells reversed signs of the disease in a mouse model of diabetes.

“This is a proof-of-concept study that provides us with a strong foundation to develop a treatment, based on patients’ own cells, for type 1 diabetes and severe type 2 diabetes,” said study lead author Dr. Dr. Joe Zhou, professor of regenerative medicine and 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, causing diabetes and its many 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 Americans lack enough beta cells due to severe type 2 diabetes. Current treatments in such cases include manual and portable pump insulin injections, which have multiple drawbacks, including pain, potentially inefficient glucose control, and the need to use cumbersome equipment.

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

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

“The stomach makes its own hormone-secreting cells, and stomach cells and pancreatic cells are adjacent in the embryonic stage of development, so in that sense, it’s not entirely surprising that gastric stem cells can become so easily into beta-type insulin-secreting cells,” said Dr. Zhou.

Attempts to reproduce these results using human gastric stem cells, which can be relatively easily collected from patients in an outpatient procedure called endoscopy, have been held back by several technical hurdles. However, in the new study, led by first author Dr. Xiaofeng Huang, a professor of molecular biology in medicine at Weill Cornell Medicine, the researchers ultimately achieved success.

After turning human gastric stem cells into beta-like cells, the team grew the cells in small clumps called organoids and found that these organ-like pieces of tissue quickly became glucose-sensitive, responding with insulin secretions. When transplanted into diabetic mice, the beta-like organoids functioned largely as real pancreatic beta cells would, secreting insulin in response to increases in blood glucose and thus keeping blood glucose levels stable. . The transplants also continued to function for as long as the researchers monitored them (six months), suggesting good durability.

Dr. Zhou said that he and his lab still need to optimize their method in a number of ways before it can be considered for clinical use. Necessary improvements include methods for scaling up beta cell production for human transplants and beta-like cell modifications to make them less vulnerable to the type of immune attack that initially kills beta cells in patients with type 1 diabetes.

Ultimately, the researchers hope to develop a technique that allows for the relatively easy harvesting of gastric stem cells from patients, followed by transplantation, weeks later, of insulin-secreting organoids that regulate blood sugar levels without the need for additional medication. .