Public release date: 4-Jul-2013 [ | E-mail | Share ]

Contact: Dr. Sibylle Kohlstdt s.kohlstaedt@dkfz.de Helmholtz Association of German Research Centres

CHARGE syndrome* is a severe developmental disorder affecting multiple organs. It affects 1 in 8500 newborns worldwide. The majority of patients carry a mutation in a gene called CHD7. How this single mutation leads to the broad spectrum of characteristic CHARGE symptoms has been a mystery.

CHD7 encodes a so-called chromatin remodeler, an important class of epigenetic regulators. DNA is wound around bead-like nucleosomes consisting of histone proteins. The string of beads is then twisted into a structure called chromatin. The more nucleosomes that occupy a gene, the less active it is. Chromatin remodelers like CHD7 are essential for the regulation of gene activity because they create nucleosome-free regions in the regulatory sequences of genes. Thus, a mutation in a gene coding for a chromatin remodeler may lead to a wide pattern of misregulated genes.

Dr. Haikun Liu's lab at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is interested in the regulation of adult neural stem cells. The scientists have a particular focus on the role adult neural stem cells play in human diseases, including mental retardation and brain tumors. CHARGE patients suffer from mental retardation and learning disabilities, strongly suggesting that a central nervous defect underlies the disease.

To understand the molecular role of the CHD7 mutation in the CHARGE phenotype, the researchers created a model using genetically modified mice. These animals permit the scientists to switch off the CHD7 gene uniquely in neural stem cells at specific developmental stages. This permitted the scientists to follow how CHD7-deficient cells proliferate, differentiate and mature over the entire lifespan of the animal.

The work led to an exciting finding: by switching off CHD7 in either fetal or adult neural stem cells, the scientists observed that the mutant cells behaved in a common way: They could not efficiently differentiate into mature neurons, which are the basic functional unit in the brains of humans and other animals. Mature neurons normally have a very complex morphology, allowing them to create networks in the brain which are important for processing information. Neurons with the mutant form of CHD7, however, seem to be incapable of forming networks.

Most strikingly, Liu and colleagues found that exercise fully rescued this phenotype in the hippocampus, the core region of the brain responsible for learning and memory. They allowed the CHD7 deficient animals to exercise on a running wheel, which rodents love to do. After the running exercise the CHD7 mutant neurons were fully rescued: They were able to create functioning networks.

That running causes a dramatic increase in neurogenesis in adults has been confirmed in animals and humans. "We were extremely excited to see that the CHD7 deficiency in a cell can be bypassed via an unknown mechanism provoked by exercise involving running. Now, we are eagerly working to find the underlying mechanism," says Haikun Liu. The neuroscientist believes this discovery will lead to a better understanding of the disease, possibly even pointing to a way to reactivate the CHD7 pathway and thus to attenuate CHARGE symptoms in human patients.

CHD7 is also an important cancer-related gene; many different types of human cancers, including lung cancer, colon cancer and brain tumors exhibit mutations in the molecule. The mechanism identified here provides a clear explanation: A mutation in CHD7 leads to a blockage of differentiation in stem cells, which is a major cause of tumorigenesis.

Read more:
Exercise rescues mutated neural stem cells

Posted on July 7, 2013, Sunday

LONDON: Scientists have for the first time created a functional human liver from stem cells derived from skin and blood and say their success points to a future where much-needed livers and other transplant organs could be made in a laboratory.

While it may take another 10 years before lab-grown livers could be used to treat patients, the Japanese scientists say they now have important proof of concept that paves the way for more ambitious organ-growing experiments.

The promise of an off-the-shelf liver seems much closer than one could hope even a year ago, said Dusko Illic, a stem cell expert at Kings College London who was not directly involved in the research but praised its success.

He said however that while the technique looks very promising and represents a huge step forward, there is much unknown and it will take years before it could be applied in regenerative medicine.

Researchers around the world have been studying stem cells from various sources for more than a decade, hoping to capitalise on their ability to transform into a wide variety of other kinds of cell to treat a range of health conditions.

There are two main forms of stem cells embryonic stem cells, which are harvested from embryos, and reprogrammed induced pluripotent stem cells (iPS cells), often taken from skin or blood.

Countries across the world have a critical shortage of donor organs for treating patients with liver, kidney, heart and other organ failure.

Scientists are keenly aware of the need to find other ways of obtaining organs for transplant.

The Japanese team, based at the Yokohama City University Graduate School of Medicine in Japan, used iPS cells to make three different cell types that would normally combine in the natural formation of a human liver in a developing embryo hepatic endoderm cells, mesenchymal stem cells and endothelial cells and mixed them together to see if they would grow.

Read more:
Scientists create human liver from stem cells

By Brenda Goodman HealthDay Reporter

WEDNESDAY, July 3 (HealthDay News) -- Japanese scientists report they've turned a cocktail of stem cells into the world's first functioning livers.

The tiny livers were created in the lab and transplanted into mice, where they grew and began to perform the same functions as human-sized livers, including metabolizing drugs and making liver-specific proteins.

Though very basic -- the experimental livers don't have all the features of full-grown organs -- it's believed to be the first time scientists have grown a three-dimensional organ in the lab using only cells.

Previously, scientists have made solid organs using stem cells that are seeded onto some kind of scaffold, either a donor organ that's been washed of all its original cells or some kind of artificial material.

But one expert said this latest approach takes the concept one step further.

"This is a different strategy to create tissues and organs," said Dr. Anthony Atala, director of the Wake Forest Institute of Regenerative Medicine, in Winston-Salem, N.C.

"The work is very important because it allows you to study how organs are created and how they give rise to more functional complex systems," Atala said. "This is a nice advance."

With further study, researchers think their technique could one day solve the critical shortage of human organs for transplantation.

"We are now assessing the applicability to other organs such as the pancreas and kidneys because they have a similar kind of developmental course as the liver. So far, we've had fascinating results," Takanori Takebe, a professor of regenerative medicine at the Yokohama City University Graduate School of Medicine, said at a press briefing.

Read more from the original source:
First Organ Grown From Stem Cells Alone: Report