Category Archives: Stem Cells

Cardiac muscle cells derived from human embryonic stem cells

The promise of embryonic stem cells lies in their ability to develop into any type of cell in the human body, which should allow us to replace tissues lost due to injury or disease. But it's one thing to generate replacement cells; it's another thing to generate entire tissues and integrate them into a functioning organ. A paper released by Nature now reports some success with turning human embryonic stem cells (hESCs) into cardiac cells and getting them to beat in synchrony with a damaged heart.

The blockage of blood vessels in the heart, either through clots or occlusion, causes the cells that rely on the blocked vessel to die off. This both weakens the heart structurally and changes the ability of the heart to beat in an organized manner, since the scar tissue that develops doesn't conduct electrical impulses. Serious arrhythmias can develop as a result of this changed activity, and these can sometimes end up causing the heartbeat to be lost entirely.

Embryonic stem cells have been used to try to repair damaged hearts for a while, starting with simple experiments where the stem cells themselves were injected. More recently, researchers have induced hESCs to form cardiac muscle cells (cardiomyocytes) before implanting them in a damaged heart (typically that of a mouse or rat). This treatment tends to increase the ability of the heart to pump blood, indicating that stem cells can reverse the weakening of the heart.

But it has been harder to get at the electrical integration of these stem cells, in part because the rodents that the researchers used have a very fast heartbeaton the order of 400-600 beats a minute. (The human heart rate is normally under 100 beats per minute.) So, the new work relied on the guinea pig, which apparently has a heart rate that is only about 200-250 beats per minute.

The authors took an hESC line and induced it to form cardiomyocytes, which were injected into injured hearts and then allowed to integrate with the injured heart for a while. Rather than focusing on blood flow, the authors tracked the development of arrhythmias. It turns out that the hESC-derived cardiomyocytes suppressed them. The guinea pigs treated with them had the lowest rate of premature ventricular contractions, or PVCs, which occur when the lower chambers of the heart beat ahead of schedule. They also went into tachycardia, or a run of rapid heartbeats, less often.

To track the behavior of the hESC-derived cardiac cells, the authors inserted a gene for a protein that becomes fluorescent in response to changes in calcium, which accompany the electrical impulses that drive a heartbeat. By tracking whether a cell was glowing, the authors could determine whether the human cells were tied to the regular guinea pig heartbeat.

Here, the results were a bit mixed. In areas where the hESC-derived cells were stuck in an area with lots of scar tissue, they tended to contract on their own, without significant influence from the guinea pig's rhythm. But in other areas where the cells were clear of nearby scar tissue, they tended to tie in nicely with the heart's overall rhythmeven when they weren't necessarily close to any guinea pig tissue.

The results are very promising, in that they show that embryonic stem cells can be used to create a large population of cardiomyocytes that can then function normally when placed back into a heart. But they also make it clear that scar tissue remains a problem in damaged hearts. Even if muscle tissue gets replaced, it won't integrate well if there's a significant amount of scar tissue around. This provides researchers with an obvious target for future efforts.

Incidentally, a number of the researchers involved in this work were based at US institutions. Early in the history of stem cell research, legislation was considered that would ban the creation of human-animal hybrids. Although it was probably written with Frankenstein-like chimeras in mind, some of it was so broadly worded that it would have banned basic safety and efficacy research such as the work described by this paper. Fortunately, it never passed, so US researchers are still able to contribute to work like this.

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Heart tissue derived from embryonic stem cells doesn't skip a beat

--Studies in mice reveal how mood-altering drugs may affect brain stem cells

Newswise Working with mice, Johns Hopkins researchers say they have figured out how stem cells found in a part of the brain responsible for learning, memory and mood regulation decide to remain dormant or create new brain cells. Apparently, the stem cells listen in on the chemical communication among nearby neurons to get an idea about what is stressing the system and when they need to act.

The researchers say understanding this process of chemical signaling may shed light on how the brain reacts to its environment and how current antidepressants work, because in animals these drugs have been shown to increase the number of brain cells. The findings are reported July 29 in the advance online publication of Nature.

What we learned is that brain stem cells dont communicate in the official way that neurons do, through synapses or by directly signaling each other, says Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicines Institute for Cell Engineerings Stem Cell Program. Synapses, like cell phones, allow nerve cells to talk with each other. Stem cells dont have synapses, but our experiments show they indirectly hear the neurons talking to each other; its like listening to someone near you talking on a phone.

The indirect talk that the stem cells detect is comprised of chemical messaging fueled by the output of neurotransmitters that leak from neuronal synapses, the structures at the ends of brain cells that facilitate communication. These neurotransmitters, released from one neuron and detected by a another one, trigger receiving neurons to change their electrical charges, which either causes the neuron to fire off an electrical pulse propagating communication or to settle down, squelching further messages.

To find out which neurotransmitter brain stem cells can detect, the researchers took mouse brain tissue, attached electrodes to the stem cells and measured any change in electrical charge after the addition of certain neurotransmitters. When they treated the stem cells with the neurotransmitter GABA a known signal-inhibiting product the stem cells electrical charges changed, suggesting that the stem cells can detect GABA messages.

To find out what message GABA imparts to brain stem cells, the scientists used a genetic trick to remove the gene for the GABA receptor the protein on the surface of the cell that detects GABA only from the brain stem cells. Microscopic observation of brain stem cells lacking the GABA receptor over five days showed these cells replicated themselves, or produced glial cells support cells for the neurons in the brain. Brain stem cells with their GABA receptors intact appeared to stay the same, not making more cells.

Next, the team treated normal mice with valium, often used as an anti-anxiety drug and known to act like GABA by activating GABA receptors when it comes in contact with them. The scientists checked the mice on the second and seventh day of valium use and counted the number of brain stem cells in untreated mice and mice treated with the GABA activator. They found the treated mice had many more dormant stem cells than the untreated mice.

Traditionally GABA tells neurons to shut down and not continue to propagate a message to other neurons, says Song. In this case the neurotransmitter also shuts off the stem cells and keeps them dormant.

The brain stem cell population in mice (and other mammals, including humans) is surrounded by as many as 10 different kinds of intermingled neurons, says Song, and any number of these may be keeping stem cells dormant. To find out which neurons control the stem cells, the researchers inserted special light-activating proteins into the neurons that trigger the cells to send an electrical pulse, as well as to release neurotransmitter, when light shines on them. By shining light to activate a specific type of neuron and monitoring the stem cells with an electrode, Songs team showed that one of the three types of neurons tested transmitted a signal to the stem cells causing a change in electrical charge in the stem cells. The neurons messaging the stem cells are parvalbumin-expressing interneurons.

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Brain's Stem Cells "Eavesdrop" to Find Out When to Act

ANN ARBOR In the first human study of its kind, researchers found that using stem cells to re-grow craniofacial tissues mainly bone proved quicker, more effective and less invasive than traditional bone regeneration treatments.

Researchers from the University of Michigan School of Dentistry and the Michigan Center for Oral Health Research partnered with Ann Arbor-based Aastrom Biosciences Inc. in the clinical trial, which involved 24 patients who required jawbone reconstruction after tooth removal.

Patients either received experimental tissue repair cells or traditional guided bone regeneration therapy. The tissue repair cells, called ixmyelocel-T, are under development at Aastrom, which is a UM spinout company.

For a video of the procedure, see: http://youtu.be/lWu_DEJfZVk

In patients with jawbone deficiencies who also have missing teeth, it is very difficult to replace the missing teeth so that they look and function naturally, said Darnell Kaigler, principal investigator and assistant professor at the UM School of Dentistry. This technology and approach could potentially be used to restore areas of bone loss so that missing teeth can be replaced with dental implants.

William Giannobile, director of the Michigan Center for Oral Health Research and chair of the UM Department of Periodontics and Oral Medicine, is co-principal investigator on the project.

The treatment is best suited for large defects such as those resulting from trauma, diseases or birth defects, Kaigler said. These defects are very complex because they involve several different tissue types bone, skin, gum tissue and are very challenging to treat.

The main advantage to the stem cell therapy is that it uses the patients own cells to regenerate tissues, rather than introducing man-made, foreign materials, Kaigler said.

The results were promising. At six and 12 weeks following the experimental cell therapy treatment, patients in the study received dental implants. Patients who received tissue repair cells had greater bone density and quicker bone repair than those who received traditional guided bone regeneration therapy.

In addition, the experimental group needed less secondary bone grafting when getting their implants.

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Stem Cell Therapy Could Offer New Hope For Head, Mouth Injuries, Defects

When transplanted into guinea pig hearts, human heart muscle cells (pictured) can beat in time with resident cells.

MEDIMAGE / SPL

Damaged skin and liver can often repair themselves, but the heart rarely heals well and heart disease is the world's leading cause of death. Research published today raises hopes for cell therapies, showing that heart muscle cells differentiated from human embryonic stem cells can integrate into existing heart muscle[1].

What we have done is prove that these cells do what working heart muscles do, which is beat in sync with the rest of the heart, says Chuck Murry, a cardiovascular biologist at the University of Washington in Seattle, who co-led the research.

It has been difficult to assess cell therapies in animal models because human cells cannot keep up with the heart rates of some small rodents. Cardiomyocytes derived from human embryonic stem (ES) cells typically beat fewer than 150 times a minute. External electrical stimulation can increase that rate, but only up to about 240 beats per minute, says Michael LaFlamme, a cardiovascular biologist at the University of Washington and the other co-leader on the project. Rats and mice have heart rates of around 400 and 600 beats per minute, respectively.

However, guinea pigs have a heart rate of 200250 beats per minute, near the limit for human cardiomyocytes. After working out ways to suppress guinea pigs immune systems so that they would accept human cells, Murry, LaFlamme and their co-workers began transplantation experiments. They also devised a way to make assessing electrical activity straightforward: using recent genetic-engineering technology, they inserted a sensor gene into the human ES cells so that cardiomyocytes derived from them would fluoresce when they contracted.

From the first experiment with the sensor in guinea pigs, it was obvious that the transplanted cells were beating in time with the rest of the heart, says LaFlamme. When he looked into the chest cavity, the heart was flashing back at us, he says.

The human cells seemed to aid healing: four weeks after the researchers killed regions of the guinea pigs hearts to simulate a heart attack, the hearts of animals that received cardiomyocytes exhibited stronger contractions than those that received other cell types. And cardiomyocyte transplants did not seem to cause irregular heartbeats, a common concern for cell-replacement therapy in the heart. In fact, the transplants seemed to suppress arrhythmias.

But it will be a long road from demonstrating this sort of integration to demonstrating possible therapeutic benefits, says Glenn Fishman, a cardiologist at New York University Langone School of Medicine, who was not involved in the work. The conclusion that the human cells can connect with the guinea pig tissue is true, he says, but the clinical implications are a bit of a stretch.

Cardiomyocytes engrafted in only a tiny percentage of scar tissue, Fishman explains, and the area seems too small to produce much additional pumping force. He suspects that the benefits seen stem from the 'paracrine effect', in which transplanted cells secrete factors that rejuvenate damaged host tissue. In fact, many researchers are exploring such strategies to prompt damaged heart tissue to restore itself, he says.

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Guinea pig hearts beat with human cells

(Credit: ANNE-CHRISTINE POUJOULAT/AFP/Getty Images)

By Michelle Durham

PHILADELPHIA (CBS) - Scientists at the University of Pennsylvania have teamed up with their counterparts all over the world, working to develop human organs from the stem cells of the patient.

Using a 3-D printer, and other tools, their goal is to eradicate the risk of rejection by building organs that wont require the immunosuppressant drugs current patients have to take.

Professor of Innovation in the Department of Bioengineering at the University of Pennsylvania, Dr. Christopher Chen says he and his colleagues have been working hard on using stem cells to engineer tissues.

One of the big limitations for being able to assemble the cells into larger structures such as hearts or livers [is that] once you form a tissue that is larger then a certain size all the cells in the center of that block will starve because they are not getting access to oxygen or blood, explains Dr. Chen.

Postdoctoral fellow Jordan Miller who works with Chen saw an exhibit featuring donated human organs filled with silicone so Miller wondered if he could create the pathways for the blood flow first and then build the organs around it.

Right now they can make pathways the size of a pinky, but Chen and Miller hope that in 10 years time the technology will be advanced enough to create an organ from these gels in their lab.

But it will be many more years before they can be transplanted into a patient.

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Scientists Work To Develop Human Organs From Stem Cells

ScienceDaily (Aug. 2, 2012) UCLA stem cell researchers have found for the first time a surprising and unexpected plasticity in the embryonic endothelium, the place where blood stem cells are made in early development.

Scientists found that the lack of one transcription factor, a type of gene that controls cell fate by regulating other genes, allows the precursors that normally generate blood stem and progenitor cells in blood forming tissues to become something very unexpected -- beating cardiomyocytes, or heart muscle cells.

The finding is important because it suggests that the endothelium can serve as a source of heart muscle cells. The finding may provide new understanding of how to make cardiac stem cells for use in regenerative medicine, said study senior author Dr. Hanna Mikkola, an associate professor of molecular, cell and developmental biology in Life Sciences and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

"It was absolutely unbelievable. These findings went beyond anything that we could have imagined," Mikkola said. "The microenvironment in the embryonic vasculature that normally gives rise to blood cells can generate cardiac cells when only one factor, Scl, is removed, essentially converting a hematopoietic organ into a cardiogenic organ."

The two-year study is published Aug. 3, 2012 in the peer-reviewed journal Cell.

The findings were so surprising, in fact, that Mikkola and her team did not want to believe the results until all subsequent assays proved the finding to be true, said Amelie Montel-Hagen, study co-first author and a post-doctoral fellow.

"To make sure we had not switched the samples between blood forming tissues and the heart we ran the experiments again and repeatedly got the same results," Montel-Hagen said. "It turns out Scl acts as a conductor in the orchestra, telling the other genes in the endothelium who should be playing and who shouldn't be playing."

The team used microarray technology to determine which genes were "playing" in embryonic endothelium to generate blood stem and progenitor cells and found that in the absence of Scl, the genes required for making cardiomyocytes were activated instead, said study co-first author Ben Van Handel, a post-doctoral fellow.

The lone difference was that Scl was missing in the process that resulted in the fate switch between blood and heart.

"Scl has a known role as a master regulator of blood development and when we removed it from the equation, no blood cells were made," Van Handel said. "That the removal of Scl resulted in fully functional cardiomyocytes in blood forming tissues was unprecedented."

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Embryonic blood vessels that make blood stem cells can also make beating heart muscles