Vascularized islets of Langerhans
Pancreatic substitute can be grown in a test tube
Julia Bondar, Copper News
Experiments on growing pancreatic islets together with vessels directly "in vitro" were crowned with success. This discovery is fundamentally important for the successful transplantation of pancreatic islet cells in type I diabetes.
The National Science Foundation has funded a multi-university study led by scientists from the University of Pittsburgh Swanson School of Engineering, who are studying the use of human pluripotent stem cells (hpSC) to create pancreatic islets in the laboratory. The main objective of the study is to develop a method for growing vascularized islets in vitro, in vitro, which, according to the researchers, will lead to an increase in the viability of islet cells and enhance their function after transplantation.
"This is the first successful attempt to create in vitro vascularized organoids – pancreatic islets from hPSCs," explains Ipsita Banerjee, head of the study. "Thanks to joint efforts, we have developed a method for implanting fragments of blood vessels into islets. By vascularizing the islets before they are transplanted into the body, they are more likely to survive and can regulate blood glucose levels faster."
What are islands and why are they vital?
Tiny clusters of cells called Langerhans islands are located throughout the pancreas, and allow the organ to produce insulin. Groups of such cells were discovered back in 1869 by the scientist Paul Langerhans, after whom they were named. Islet cells are concentrated mainly in the tail of the pancreas, and make up 2% of the body weight. In total, there are about 1 million islets in parenchyma.
It was revealed that in newborns, islets occupy 6% of the total mass of the organ. As the body matures, the proportion of structures with endocrine activity decreases. By the age of fifty, only 1-2% of them remain. During the day, the islets of Langerhans secrete about 2 milligrams of insulin.
Type I diabetes causes the immune system to destroy these islets. As a result, patients must take insulin daily to maintain their blood sugar levels. Too high sugar levels can lead to hyperglycemia, diabetic ketoacidosis and, if these conditions are not stopped, to death. Patients should independently regulate their blood sugar levels throughout their lives. Or look for an opportunity to replace the non–functioning pancreas or its active part - the islets of Langengars.
Why do islands need vessels?
The islets of the pancreas have very high oxygen requirements. When transplanting, they need to be "connected" to the vessels of the recipient body as soon as possible, otherwise they will begin to lose their ability to regulate blood glucose levels very quickly and die off. Researchers began to look for new methods to accelerate the vascularization of islets after transplantation, and came to the conclusion that it is easier to "grow" vessels even before transplantation, in a test tube, right inside a group of islet cells.
In the experiment, a new structuring system was used – a special hydrogel to create a three-dimensional configuration of a cell culture that mimics the way the pancreas is formed naturally.
"Hydrogel is like scaffolding, and it helps to build up the cells of the structure in three–dimensional space," says Dr. Banerjee. "Usually pluripotent stem cells are a structure of uncontrolled configuration, however, using a hydrogel developed by our employee at Arizona State, we can create an exact multicellular architecture called "spheroids". Unlike the usual two-dimensional culture of islet cells grown in a Petri dish, islet spheroids grown on hydrogel are completely identical to those structures that are formed naturally in the body."
In addition to being used directly for transplantation, the creation of viable vascularized pancreatic islets outside the body can become a valuable tool for testing the effectiveness and toxicity of new drugs for the treatment of the pancreas. In addition, vascularization of organelles in vitro opens up new horizons in the field of transplantation.
"The principles of pre–designing vascularization before transplantation can be applied to any type of tissue, not just in the case of the pancreas," says Dr. Banerjee. "When donor islets are used for transplantation, some of them die as a result of the procedure. We expect that the measures we take in the laboratory before new cells are transplanted into the patient's body will be of great importance for the next generation of regenerative medicine."
Previous research
Attempts to stimulate the vascularization of islet cells in vitro have been carried out before. So, in 2011, the results of an experiment by American scientists from Boston University, Brown University, Alpert Medical School were published, in which they tested the assumption that bone marrow stem cells stimulate angiogenesis in pancreatic islets. To test this hypothesis, human islets (100 per 1 ml) were cultured separately (control) or together with whole human bone marrow (one million cells per 1 ml) for 210 days. When evaluated at the end of cultivation, it was found that during co-cultivation, the content of angiogenesis factors such as VEGF-a (535 vs 2 pg/mL), PDGF (280.79 vs 0 pg/mL), KGF (939 vs 8 pg/mL), TIMP-1 (4592 vs 4332) significantly increases pg/mL) and angiogenin (506 vs 97 pg/mL). At the same time, the content of angiopoietin-2 was lower than in the control (5 vs 709 pg/mL). If these proangiogenic factors are removed during co-cultivation, the islets vascularization caused by SC also decreases, which indicates a paracrine mechanism of action of these cells.
In stem cell-induced vascularization, significant dispersion of endothelial cells and islet growth were observed. Those islets that decreased in size were characterized by weak vascularization. During the entire period of cultivation, insulin release was observed, which indicates the preservation of the function of the islets in interaction with stem cells. Moreover, during co-cultivation, there was a significant increase in the gene expression of insulin and glucagon compared to the control – by 28.66 and 24.4 times, respectively. This indicates that SCS also stimulate the regeneration of endocrine cells.
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04.09.2017