venerdì 30 agosto 2013

Scientists grow mini brains from stem cells

We've seen beating heart tissue, windpipes and bladders all grown from stem cells. Now researchers have taken another important step forward by growing mini brains from these programmable cells.
They're not actually functioning brains -- in the same way that a car with the engine on its roof or wheels on its hood isn't a drivable vehicle -- but the parts are there, and that's an important scientific advancement, according to Juergen Knoblich, senior author of a new study on using stem cells to grow brain tissue.
Scientists have created what they are calling "cerebral organoids" using stem cells. These pea-sized structures are made of human brain tissue, and they can help researchers explore important questions about brain development and disorders that occur during these first stages of life.
The organoids, as described in the journal Nature, have components resembling those of a brain of a 9- or 10-week-old embryo, said lead study author Madeline Lancaster, a researcher at the Institute of Molecular Biotechnology at the Austrian Academy of Science in Vienna, at a press briefing Tuesday.
She and colleagues have created hundreds of these organoids.
At this early stage of human development, several key regions of the brain are already distinctive features, including the dorsal cortex, the ventral forebrain, the choroid plexus -- which generates cerebrospinal fluid -- and regions that resemble the midbrain and hindbrain. Lancaster and colleagues say they've identified some of those same regions in these new mini brains.
However, these regions did not naturally fall into place in the stem cell models the same way they would have in a normal brain.
"These different regions are not organized in the same kind of fashion that you would see in the developing embryo," Lancaster said.
The organoids also lack certain features that human embryonic brains at 9 weeks do have: most importantly, the cerebellum, which is involved in motor movement. Also, the hippocampus, a seahorse-shaped structure crucial for memory, was rarely detected in these brain-like structures.
Researchers used human embryonic stem cells and induced pluripotent stem cells (IPS cells) for this research. Both embryonic stem cells and IPS cells have the ability to turn into any part of the body. But embryonic stem cells are very controversial because in the process of retrieving them for research, the 4- or 5-day-old embryo they are taken from is destroyed. IPS cells don't come with the same controversy because scientists take a cell -- typically a skin cell -- then coax it using a chemical bath to revert to a state that resembles a developing embryo.
There did not appear to be an obvious difference between organoids derived from embryonic stem cells and those produced from IPS cells, said Knoblich, also of the Austrian Academy of Science.
Study authors found variability in the organoids they generated; occasionally some of the brain regions they were studying failed to appear.
Lancaster attempted to direct the development of these regions in some of the organoids by applying growth factors, substances that promote the proliferation of cells. Surprisingly, when she tried to grow the mini brains with more dorsal cortex tissue, the resulting structures had less of this tissue than the organoids that had developed on their own.
"We actually think that the cross-talk between these different regions -- the communication between these different brain regions within the organoids -- is really important for each individual region's development," she said.
The researchers used this model to look at a neurodevelopmental disease called microcephaly, a disorder in which the size of the brain is reduced. The brain region they were most interested in exploring, the dorsal cortex, is the region most highly impacted by this disease.
Researchers grew some of these organoids using cells from a patient who had a genetic form of microcephaly, and compared them with the mini brains derived from healthy participants' cells.
In the organoids made from the microcephaly patient's cells, it appeared that more stem cells had been turned into neurons -- a process called differentiation -- than in the mini brains derived from healthy patients' cells. This suggests that in people with this condition, neurons prematurely differentiate, which could be the mechanism behind this form of the disease, said Oliver Brustle at the Life & Brain Centre at University of Bonn, in an accompanying article in Nature.
This research builds on other studies that have attempted to model brain tissue from stem cells. A 2008 study showed that mouse embryonic stem cells could be coaxed into producing "waves" of neurons. A different research group showed in 2012 that primitive eye structures and stratified retinas could form from embryonic stem cells taken from both mice and humans. Study authors said they have no intention of growing a full-sized human brain.
"It is very clear that our system is not optimized for generating an entire brain, and that is also in no way our goal," Knoblich said.
As for growing a brain structure from stem cells that's capable of conscious thought, Knoblich said this would likely not be possible, or desirable.
Although the organoids are an important step forward, the researchers are nowhere near being able to model circuits found in the functional central nervous system. Moreover, Knoblich said, sensory input is required for such functional circuits to form. A classical experiment showed that the optic cortex will not organize properly if it does not have input from an eye, he said.
Knoblich is also pessimistic about the idea of growing brain structures from stem cells with the intention of replacing faulty ones in human patients. The brain is so complex, and its regions so intimately integrated, that it would be difficult to repair any specific part through substitution.
A more promising possibility, he said, would be to put the stem cells directly into the patient and let them organize themselves. But the future of this line of research is still unknown.
Brustle, who was not involved in this research, called the study "remarkable" and noted that it "clearly puts neural aggregation cultures on the map of research tools for both developmental biology and biomedicine."
That's a lot from a little tissue.

Architect, stem cell pioneer and Nobel laureate made life senators

Rome, 30 August (AKI) - World-famous architect Renzo Piano, physics Nobel Prize-winner Carlo Rubbia, stem-cell pioneer Elenea Cattaneo and conductor Claudio Abbado were appointed Life Senators on Friday by Italian president Giorgio Napolitano. Piano, Rubbia, Cattaneo and Abbado had distinguished themselves for "for outstanding merits in the social, scientific, artistic and literary field," Napolitano stated. They join former Italian president Carlo Azeglio Ciampi and ex-premier Mario Monti in the upper house of parliament. Announcing the appointments, Napolitano said he was filling gaps "sadly left" by the deaths over the past year of seven-times premier Giulio Andreotti, Nobel medicine laureate Rita Levi-Montalcini, former prime minister Emilio Colombo and car designer Sergio Pininfarina. Piano was one of the creators of the futuristic Pompidou Centre in Paris, and Abbado is former director of the Berlin Philharmonic Orchestra.

lunedì 26 agosto 2013

Mending a Broken Heart? Scientists Transform Non-Beating Human Cells Into Heart-Muscle Cells

In the aftermath of a heart attack, cells within the region most affected shut down. They stop beating. And they become entombed in scar tissue. But now, scientists at the Gladstone Institutes have demonstrated that this damage need not be permanent -- by finding a way to transform the class of cells that form human scar tissue into those that closely resemble beating heart cells.
Last year, these scientists transformed scar-forming heart cells, part of a class of cells known as fibroblasts, into beating heart-muscle cells in live mice. And in the latest issue of Stem Cell Reports, researchers in the laboratory of Gladstone Cardiovascular and Stem Cell Research Director Deepak Srivastava, MD, reveal that they have done the same to human cells in a petri dish.
"Fibroblasts make up about 50% of all cells in the heart and therefore represent a vast pool of cells that could one day be harnessed and reprogrammed to create new muscle," said Dr. Srivastava, who is also a professor at the University of California, San Francisco, with which Gladstone is affiliated. "Our findings here serve as a proof of concept that human fibroblasts can be reprogrammed successfully into beating heart cells."
In 2012, Dr. Srivastava and his team reported in the journal Nature that fibroblasts could be reprogrammed into beating heart cells by injecting just three genes, together known as GMT, into the hearts of live mice that had been damaged by a heart attack. They reasoned that the same three genes could have the same effect on human cells. But initial experiments on human fibroblasts from three sources -- fetal heart cells, embryonic stem cells and neonatal skin cells -- revealed that the GMT combination alone was not sufficient.
"When we injected GMT into each of the three types of human fibroblasts, nothing happened -- they never transformed -- so we went back to the drawing board to look for additional genes that would help initiate the transformation," said Gladstone Staff Scientist Ji-dong Fu, PhD, the study's lead author. "We narrowed our search to just 16 potential genes, which we then screened alongside GMT, in the hopes that we could find the right combination."
The research team began by injecting all candidate genes into the human fibroblasts. They then systematically removed each one to see which were necessary for reprogramming, and which were dispensable. In the end, the team found that injecting a cocktail of five genes -- the 3-gene GMT mix plus the genes ESRRG and MESP1 -- were sufficient to reprogram the fibroblasts into heart-like cells. They then found that with the addition of two more genes, called MYOCD and ZFPM2, the transformation was even more complete. To help things along, the team initiated a chemical reaction known as the TGF-ß signaling pathway during the early stages of reprogramming, which further improved reprogramming success rates.
"While almost all the cells in our study exhibited at least a partial transformation, about 20% of them were capable of transmitting electrical signals -- a key feature of beating heart cells," said Dr. Fu. "Clearly, there are some yet-to-be-determined barriers preventing a more complete transformation for many of the cells. For example, success rates might be improved by transforming the fibroblasts within living hearts rather than in a dish -- something we also observed during our initial experiments in mice."
The immediate next steps are to test the five-gene cocktail in hearts of larger mammals, such as pigs. Eventually, the team hopes that a combination of small, drug-like molecules could be developed to replace the cocktail, offering a safer and easier method of delivery.
"With more than five million heart attack survivors in the United States, who have hearts that are no longer able to beat at full capacity, our findings -- along with recently published findings from our colleagues -- come at a critical time," added Dr. Srivastava. "We've now laid a solid foundation for developing a way to reverse the damage -- something previously thought impossible -- and changing the way that doctors may treat heart attacks in the future."

Cancer scientists discover novel way gene controls stem cell self-renewal


(TORONTO, Canada – Aug. 25, 2013) – Stem cell scientists at the Princess Margaret Cancer Centre have discovered the gene GATA3 has a role in how blood stem cells renew themselves, a finding that advances the quest to expand these cells in the lab for clinical use in bone marrow transplantation, a procedure that saves thousands of lives every year.
The research, published online today in Nature Immunology, provides an important piece in the puzzle of understanding the mechanisms that govern the blood stem cell self-renewal process, says principal investigator Norman Iscove, Senior Scientist at the Princess Margaret, University Health Network (UHN). Dr. Iscove is also an investigator at UHN's McEwen Centre for Regenerative Medicine and a Professor in the Faculty of Medicine, University of Toronto.
"Researchers have known for a long time that stem cells can increase their numbers in the body through self-renewal; however, it has proven very difficult to establish conditions for self-renewal in the laboratory," says Dr. Iscove. Indeed, he explains, the quest to do so has been a holy grail for stem cell researchers because the very effectiveness, safety and availability of the transplantation procedure depend on the number of stem cells available to transplant.
In the lab and using genetically engineered mice, the Iscove team zeroed in on GATA3 and determined that interfering with its function causes stem cells to increase their self-renewal rate and thereby results in increased numbers of stem cells. Dr. Iscove expects scientists will be able to use this new information to improve their ability to grow increased numbers of blood stem cells for use in bone marrow transplantation and possibly, gene therapy.
Dr. Iscove's research is a new page in the growing volume of stem cell science that began here in 1961 with the ground-breaking discovery of blood-forming stem cells by Drs. James Till and the late Ernest McCulloch. Their discovery changed the course of cancer research and laid the foundation for bone marrow transplantation in leukemia patients, as well as for many other types of current disease research. The research published today was funded by the Terry Fox Foundation, the Canadian Cancer Society Research Institute, the Canadian Institutes of Health Research, the Stem Cell Network, the McEwen Centre for Regenerative Medicine, The Princess Margaret Cancer Foundation, The Campbell Family Institute for Cancer Research and the Ontario Ministry of Health and Long-term care.