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Left: Pancreatic beta cell cluster derived from human pluripotent stem cells in a lab box. The insulin-producing cells are marked in green. Red indicates the presence of PDX1, a key protein involved in the production of insulin. Right: When islet cells generated from human stem cells in the laboratory are transplanted into mice, they form clusters and begin to produce the three key hormones for the regulation of islet blood sugar. normal pancreatic Green cells are insulin-producing beta cells, red blood cells are glucagon-producing alpha cells, and blue cells are somatostatin-producing delta cells. Credit: Hebrok Lab / UCSF
Researchers at the University of San Francisco (UC San Francisco) for the first time transformed human stem cells into mature insulin-producing cells, a major breakthrough in efforts to develop a cure. type 1 diabetes (T1).
Replacing those cells, which are lost in patients with T1 diabetes, has long been a dream of regenerative medicine, but until now, scientists had not been able to determine how to produce cells in a lab dish that work as in healthy adults.
"We can now generate insulin-producing cells that look and act much like the beta cells in the pancreas that you and I have in our body. This is a crucial step towards our goal of creating cells that could be transplanted into diabetic patients, "said Matthias Hebrok, PhD, Hurlbut-Johnson Distinguished Professor of Diabetes Research at UCSF and Director of the UCSF Diabetes Center. Hebrok was the principal author of the new study published on February 1, 2019 in Nature Cell Biology.
T1 diabetes is an autoimmune disease that destroys insulin-producing pancreatic beta cells, usually in childhood. Without insulin's ability to regulate glucose levels in the blood, peaks in blood sugar can severely damage organs and eventually lead to death. This condition can be managed by regularly taking insulin injections during meals, but people with type 1 diabetes still suffer serious health consequences, such as kidney failure, heart disease and a stroke.
Patients facing potentially life-threatening complications of their disease may be eligible for a pancreas transplant from a deceased donor, but they are rare and waiting time is long: about 1.5 million people living with type 1 diabetes in the United States, about 1,000 people receive a pancreas transplant in a given year. The procedure is also risky: recipients have to take immunosuppressive drugs for life and many of the transplants fail for one reason or another. Transplants of only pancreatic "islets" – clusters of cells containing healthy beta cells – are currently undergoing clinical trials, but still rely on pancreas from deceased donors.
That's why Hebrok and other diabetes researchers have long hoped to use stem cells to produce healthy beta cells in the laboratory that can be transplanted into patients without waiting for pancreas or islet transplantation. But for years, scientists have been unable to understand how to program stem cells into fully mature beta cells.
"The cells we and others produced were stuck in an immature stage where they were unable to respond properly to blood glucose levels and to secrete insulin properly. This has been a major bottleneck for the industry, "said Hebrok.
In the new study, Hebrok and his colleagues, led by Gopika Nair, PhD, a postdoctoral fellow, have realized that the key to ensuring that beta cells grown in the lab reach full maturity is a neglected facet of beta cell development – the process physical by which the cells separate. from the rest of the pancreas and form the so-called islets of Langerhans.
"A key principle in biology is that form follows function, so we decided that islet formation could be an important process for beta cells to mature properly," Nair said.
When the researchers duplicated this process in laboratory cans by artificially separating partially differentiated pancreatic stem cells and reforming them into clusters resembling islets, cell development suddenly progressed. Not only did beta cells begin to react to blood sugar levels, more like mature insulin-producing cells, but the entire "neighborhood" of the islet – including alpha and delta cells less well understood – also seemed to develop in a way never seen before. laboratory setting.
Scientific image of islet cells generated from transplanted laboratory human stem cells in mice.
The researchers then transplanted these lab-grown "islets" into healthy mice and found that they were working in just a few days – producing insulin in response to blood glucose, much like the islets of the liver. 'animal.
In collaboration with bioengineers, geneticists and other UCSF colleagues, the Hebrok team is already working to move regenerative therapies from dream to reality, for example by using genetic modification. CRISPR to make these cells transplantable without the need for immunosuppressive drugs, or by looking for drugs that could restore islet function in patients with T1 diabetes by protecting and developing their remaining few beta cells to revive the production of diabetes. pancreatic insulin.
"Current therapies such as insulin injections only treat the symptoms of the disease," Nair said. "Our work indicates several exciting ways to finally find a cure."
"We are finally able to move forward on several fronts that were previously closed to us," Hebrok added. "The possibilities seem endless."
This article has been republished from documents provided by the University of California at San Francisco. Note: Content may have changed for length and content. For more information, please contact the cited source.
Reference:
Nair, G.G., Liu, J.S., Russ, H.A., Tran, S., Saxton, M.S., Chen, R.,. . . Hebrok, M. (2019). Recapitulation of cultured endocrine cells promotes maturation of β-cells derived from human stem cells. Nature Cell Biology, 21(2), 263-274. doi: 10.1038 / s41556-018-0271-4
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