Beta cells from the Wolfram subjects produced less insulin in the culture dish and secreted less insulin into the bloodstream of the mice when they were challenged with high blood-sugar levels.Ī key finding was that these beta cells showed elevated markers of ER stress. They implanted both Wolfram and control iPS cell-derived beta cells under the kidney capsule of immuno-compromised mice. The researchers differentiated the iPS cells from the Wolfram subjects and the controls into beta cells, an intricate process that took several weeks. An iPS cell line generated from a healthy individual was used as a normal control. The researchers at NYSCF “reprogrammed,” or reverted, the skin cells to an embryonic-like state to become iPS cells. Additional cell lines were obtained from Coriell Institute for Medical Research. All Wolfram patients had childhood-onset diabetes requiring treatment with injected insulin, and all had vision loss. The use of drugs that reduce such stress may prove useful in the prevention and treatment of diabetes.”Ĭlinicians from the Naomi Berrie Diabetes Center recruited Wolfram syndrome patients to donate a skin sample. “Our ability to create functional insulin-producing cells using stem-cell techniques on skin cells from patients with Wolfram’s syndrome has helped to uncover the role of ER stress in the pathogenesis of diabetes. Murphy Professor of Diabetes Research and co-director of the Naomi Berrie Diabetes Center at CUMC. “This report highlights again the utility of close examination of rare human disorders as a path to elucidating more common ones,” said co-author Rudolph L. Solomon, co-founder and chief executive officer of the New York Stem Cell Foundation. “Utilizing stem cell technology, we were able to study a devastating condition to better understand what causes the diabetes symptoms, as well as discover possible new drug targets,” said Susan L. It also enables the testing of strategies to restore beta-cell function that may be applicable to all types of diabetes. Since all forms of diabetes are ultimately the result of an inability of pancreatic beta cells to provide sufficient insulin in response to blood sugar concentrations, this Wolfram patient stem-cell model enables analysis of a specific pathway leading to beta-cell failure in more prevalent forms of diabetes. Wolfram syndrome is a rare, often fatal genetic disorder characterized by the development of insulin-dependent diabetes, vision loss, and deafness. This human iPS-cell model represents a significant step forward in enabling the study of this debilitating disease and the development of new treatments,” said Dieter Egli, PhD, principal investigator of the study, senior research fellow at NYSCF, and NYSCF–Robertson Stem Cell Investigator. “These cells represent an important mechanism that causes beta-cell failure in diabetes. They found that a chemical, 4-phenyl butyric acid, that relieves this stress prevents the cells from failing, suggesting a potential target for clinical intervention. Next, they showed that the beta cells failed to normally secrete insulin because of protein-folding-or endoplasmic reticulum (ER)-stress. They then derived insulin-producing cells (beta cells) from these iPS cells, creating a human diabetes model in vitro. Scientists from NYSCF produced induced pluripotent stem (iPS) cells from skin samples from individuals with a rare form of diabetes, Wolfram syndrome.
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