Insulin-producing Beta Cells from Stem Cells

Scientists decipher early molecular mechanisms of differentiation

Thursday, 23 January 2014

Endodermal cells, they form organs such as lung,

liver and pancreas. Credit: IDR, Helmholtz

Zentrum München.

The Wnt/β-catenin signalling pathway and microRNA 335 are instrumental in helping form differentiated progenitor cells from stem cells. These are organized in germ layers and are thus the origin of different tissue types, including the pancreas and its insulin-producing beta cells. With these findings, Helmholtz Zentrum München scientists have discovered key molecular functions of stem cell differentiation which could be used for beta cell replacement therapy in diabetes. The results of the two studies were published in the renowned journal Development.

The findings of the scientists of the Institute of Diabetes and Regeneration Research (IDR) at Helmholtz Zentrum München (HMGU) provide new insights into the molecular regulation of stem cell differentiation. These results reveal important target structures for regenerative therapy approaches to chronic diseases such as diabetes.

During embryonic development, organ-specific cell types are formed from pluripotent stem cells, which can differentiate into all cell types of the human body. The pluripotent cells of the embryo organize themselves at an early stage in germ layers: the endoderm, mesoderm and ectoderm. From these three cell populations different functional tissue cells arise, such as skin cells, muscle cells, and specific organ cells.

Various signalling pathways are important for this germ layer organization, including the Wnt/β-catenin signalling pathway. The cells of the pancreas, such as the beta cells, originate from the endoderm, the germ layer from which the gastrointestinal tract, the liver and the lungs also arise. Professor Heiko Lickert, director of the IDR, in collaboration with Professor Gunnar Schotta of LMU München, showed that the Wnt/β-catenin signalling pathway regulates Sox17, which in turn regulates molecular programs that assign pluripotent cells to the endoderm, thus inducing an initial differentiation of the stem cells.

In another project Professor Lickert and his colleague Professor Fabian Theis, director of the Institute of Computational Biology (ICB) at Helmholtz Zentrum München, discovered an additional mechanism that influences the progenitor cells. miRNA-335, a messenger nucleic acid, regulates the endodermal transcription factors Sox17 and Foxa2 and is essential for the differentiation of cells within this germ layer and their demarcation from the adjacent mesoderm. The concentrations of the transcription factors determine here whether these cells develop into lung, liver or pancreas cells. To achieve these results, the scientists combined their expertise in experimental research with mathematical modelling.

"Our findings represent two key processes of stem cell differentiation," said Lickert.

"With an improved understanding of cell formation we can succeed in generating functional specialized cells from stem cells. These could be used for a variety of therapeutic approaches. In diabetes, we may be able to replace the defective beta cells, but regenerative medicine also offers new therapeutic options for other organ defects and diseases."

Diabetes is characterized by a dysfunction of the insulin-producing beta cells of the pancreas. Regenerative treatment approaches aim to renew or replace these cells. An EU-funded research project ('HumEn'), in which Lickert and his team are participating, shall provide further insights in the field of beta-cell replacement therapy.

The aim of research at Helmholtz Zentrum München, a partner in the German Center for Diabetes Research (DZD), is to develop new approaches for the diagnosis, treatment and prevention of major common diseases such as diabetes mellitus.

Source: Helmholtz Zentrum München

Contact: Heiko Lickert

References:

Wnt/β-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse 

Silvia Engert, Ingo Burtscher, W. Perry Liao, Stanimir Dulev, Gunnar Schotta and Heiko Lickert

Development, 2013, 140:3128-3138, doi:10.1242/dev.088765

miR-335 promotes mesendodermal lineage segregation and shapes a transcription factor gradient in the endoderm

Dapeng Yang, Dominik Lutter, Ingo Burtscher, Lena Uetzmann, Fabian J. Theis, and Heiko Lickert

Development, 2014, 141, 514-525, doi:10.1242/dev.104232

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Discovery of Genetic Switch Advances Diabetes Research

Discovery of Genetic Switch Advances Diabetes Research Monday, 20 July 2009 Scientists have identified a master regulator gene for early embryonic development of the pancreas and other organs, putting researchers closer to coaxing stem cells into pancreatic cells as a possible cure for type1 diabetes. Researchers at Cincinnati Children's Hospital Medical Center report their findings in the July 21 Developmental Cell. Besides having important implications in diabetes research, the study offers new insights into congenital birth defects involving the pancreas and biliary system by concluding both organs share a common cellular ancestry in the early mouse embryo. This discovery reverses a long standing belief that the biliary system's origin is connected to early embryonic formation of the liver, the researchers said. The pancreas regulates digestion and blood sugar, and the biliary system is vital for digestion. If the organs do not form properly during foetal development, it can be fatal. The study reports that one gene, Sox17 (a transcription factor that controls which genes are turned on or off in a cell) is the key regulator for giving instruction to cells in early mouse embryos to become either a pancreatic cell or part of the biliary system. The first author on the paper is Jason Spence, Ph.D., a research fellow in the lab of the study's senior investigator, James Wells, Ph.D., a researcher in the Division of Developmental Biology at Cincinnati Children's and associate professor of paediatrics at the University of Cincinnati College of Medicine. "We show that Sox17 acts like a toggle or binary switch that sets off a cascade of genetic events," said Dr. Wells. "In normal embryonic development, when you have an undecided cell, if Sox17 goes one way the cell becomes part of the biliary system. If it goes the other way, the cell becomes part of the pancreas." The finding advances ongoing research by Dr. Wells and his team to guide embryonic stem cells to become pancreatic beta cells, which scientists believe could be used to treat or cure type1 diabetes. The disease occurs when the immune system attacks insulin producing beta cells in the pancreas, usually destroying them beyond repair before the illness is diagnosed. "With this study showing us that turning one gene on or off in a mouse embryo instructs a cell to become pancreatic or biliary, now we'll see if that same gene, Sox17, can be used to direct an embryonic stem cell to become a biliary cell instead of a pancreatic cell. This might be used one day to replace a diseased pancreas or bile duct in people," said Dr. Wells. The study explains that Sox17 initially works in conjunction with two other genes (the transcription factors Pdx1 and Hes1) to decide which organ fate ventral foregut progenitor cells will take. Researches demonstrated that Sox17's key role begins when the mouse embryo is 8 1/2 days old. If Sox17 toggles one way, with its expression repressed by its interaction with Hes1, then Pdx1 more or less takes over to prompt formation of the ventral pancreas. If Sox17 toggles the other way to increases its expression, the gene helps set off formation of the biliary system. Dr. Wells and his colleagues are also using data from the current study to conduct experiments that should reveal what other genes are turned on or off along molecular cascade set into motion by Sox17. "Although Sox17 is the master switch, it triggers a molecular cascade of switches, and a defect in any of those can cause the whole thing to go wrong, resulting in congenital defects of the pancreas and biliary system," Dr. Wells said. Jeffrey Whitsett, M.D., executive director of the Cincinnati Children's Perinatal Institute and one of the current study's authors, said the research provides important clues for clinicians managing congenital birth defects of the pancreas and biliary system, which includes the bile ducts and gall bladder. Malformations in this region of the gastrointestinal tract can cause blockage of bile ducts or the intestines. One of the common defects is a condition called biliary atresia, in which the bile ducts are blocked, causing bile to accumulate, back up and leading to potential damage of the pancreas or liver. "Babies in neonatal intensive care frequently are born with medically challenging birth defects. The present studies help unravel the complex genetic systems controlling the formation of the gastrointestinal tract and provide the framework for future therapies of disease affecting the formation and function of the pancreas, liver, and bile ducts," Dr. Whitsett said. Reference: Sox17 Regulates Organ Lineage Segregation of Ventral Foregut Progenitor Cells Jason R. Spence, Alex W. Lange, Suh-Chin J. Lin, Klaus H. Kaestner, Andrew M. Lowy, Injune Kim, Jeffrey A. Whitsett, James M. Wells Developmental Cell, Volume 17, Issue 1, 62-74, 21 July 2009, doi:10.1016/j.devcel.2009.05.012 ......... ZenMaster

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Protein Distinguishes Fetal and Adult Stem Cells

Protein Distinguishes Fetal and Adult Stem Cells July 26, 2007 In a discovery that fills a critical gap in the understanding of stem cells, researchers have discovered a protein that fetal, but not adult, blood-forming stem cells need to replenish themselves. Finding regulatory pathways specific to fetal blood-forming cells could help scientists understand childhood leukemias and generate blood-forming cells for bone marrow transplants. Research published in the July 26, 2007, issue of Cell. Sean J. Morrison, Ph.D., HHMI investigator University of Michigan Medical School For the full story, go to: http://www.hhmi.org//news/morrison20070727.html ......... ZenMaster

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For more on stem cells and cloning, go to CellNEWS at http://www.geocities.com/giantfideli/index.html

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