TORONTO — A Canadian-led international research team has determined how to grow early-stage human heart cells from embryonic stem cells, a step that could one day allow scientists to create new tissue for repairing a person’s damaged heart.

“Probably something a little more in the near future would be that this gives us an opportunity to efficiently generate human heart cells that can be used for drug screening and drug toxicology,” said principal investigator Gordon Keller.

In other words, scientists would be able to create these early-stage heart cells – known as progenitor cells – then allow them to grow into different types of cardiac cells that could be used for drug testing right in the lab.

“A lot of people have been talking about this, but I think when you see the … relative ease we have in producing such cells, we can now start interacting with biotech companies and pharmaceutical companies,” said Keller, director of Toronto’s McEwen Centre for Regenerative Medicine at the University Health Network.

Keller stressed that this is not the first time heart cells have been grown from embryonic stem cells. What the Toronto-led lab has done is figure out the “recipe” for making embryonic stem cells give rise to distinct types of immature progenitor heart cells.

This recipe, detailed in the latest issue of the journal Nature, is believed to mimic the process that directs embryonic stem cells at life’s earliest stages to develop heart progenitor cells.

These progenitors are able to make three major cell types found in the human heart – cardiomyocytes (the ones that beat), endothelial cells and vascular smooth muscle cells that will form cardiac blood vessels.

“By isolating these cells, these progenitors, first and then allowing them to mature, we can get populations highly enriched for cells that are beating or cells that are not beating – in other words, some of the vascular cells,” Keller said.

The process involves placing human embryonic stem cells – from existing stem cell lines scientists have long had access to – in Petri dishes, adding growth factors and other substances and then culturing them in special incubators.

After five or six days, the stem cells have given rise to heart progenitor cells. Under the microscope, some of these cells can be seen to have spontaneously begun pulsing – just as certain cardiac cells work together to cause the human heart to beat as a whole.

“You can view it as the first step in heart cell development,” Keller said.

But when it comes to the idea of injecting such cells directly into a person’s heart in the hope they would grow healthy tissue to repair damage from a heart attack, Keller believes that is “a long way off.”

“That’s why we talk about tissue engineering. The notion of us taking cells that we grow in a dish and putting them straight into a heart is probably naive,” he said.

“We will have to interact with our colleagues in tissue engineering to make structures that more approximate the three-dimensional aspects of our organogenesis (production of organs).”

Still, the researchers are already planning to transplant heart progenitor cells into animals with heart damage – likely pigs or sheep – to see if they will at least mature into the three cells types they’ve been able to create in culture dishes.

Keller said U.S. colleagues included in the Nature study have injected them into laboratory mice, and they “made all three heart cells but at a very low frequency.”

In the future, he believes heart progenitors could be grown from stem cells derived from individuals. (Japanese and U.S. scientists recently reported finding a way of culturing “pluripotent” stem cells, those which give rise to all 220 cell types in the body, from people’s skin).

“In principal, one could do this from any individual,” he said.

“Our hope is that we can turn any of these pluripotent stem cells into these cardiovascular progenitors and ultimately into cardiac cells,” Keller said.

Ideally, the researchers would like to grow large numbers of progenitors and freeze them, so they could be used as needed.

“And then we don’t always have to go back to the stem cell. We already have the cell that’s poised and ready to make the heart cells.”

ScienceDaily (Apr. 23, 2008) — Dutch researchers at University Medical Center Utrecht and the Hubrecht Institute have succeeded in growing large numbers of stem cells from adult human hearts into new heart muscle cells. A breakthrough in stem cell research. Until now, it was necessary to use embryonic stem cells to make this happen.

The stem cells are derived from material left over from open-heart operations. Researchers at UMC Utrecht used a simple method to isolate the stem cells from this material and reproduce them in the laboratory, which they then allowed to develop. The cells grew into fully developed heart muscle cells that contract rhythmically, respond to electrical activity, and react to adrenaline.

“We’ve got complete control of this process, and that’s unique,” says principal investigator Prof. Pieter Doevendans. “We’re able to make heart muscle cells in unprecedented quantities, and on top of it they’re all the same. This is good news in terms of treatment, as well as for scientific research and testing of potentially new drugs.”

Doevendans will use the cultured heart muscle cells to study things like cardiac arrhythmia (abnormal heart rhythms). Stem cells from the hearts of patients with genetic heart defects can be grown into heart muscle cells in the lab. Researchers can then study the cells responsible for the condition straight away. They can also be used to test new medicines. This could mean that research into genetic heart conditions can move forward at a much faster pace. In the future, new heart muscle cells can likely be used to repair heart tissue damaged during a heart attack.

For some time now, it has been known that the heart is a source of stem cells. Although in the past researchers from other countries have succeeded in using these cells to make heart muscle cells, this always required the presence of heart muscle cells from newborn mice or rats in the growth medium. The stem cells discovered by the UMC Utrecht researchers are able to develop on their own. Heart muscle cells can also be made from embryonic stem cells. The disadvantage of this method is that the yield is low, because not all cells develop into muscle cells. Also, the ethical considerations of isolating stem cells from embryos are the subject of controversy.

The findings are published in the journal Stem Cell Research.

Adapted from materials provided by University Medical Center Utrecht.

Government advisors meet this week to discuss designs for embryonic stem cell human experiments.

NEW YORK (CNNMoney.com) — The Food and Drug Administration looks like it’s bowing to the inevitable this week and drawing the blueprint for the first-ever human experiments with human embryonic stem cells.

FDA advisors meet Thursday and Friday to begin to design how these embryonic stem cell tests will be conducted. It’s an important regulatory step that could lead to human testing as early as this year. So far, biotechs have tested their spinal-cord drugs in animals, not people.

“[The FDA meeting] is the first step towards clinical trials,” said Laurie Zoloth, professor of medical humanities and bioethics at Northwestern University. “It’s an important moment. And it’s only the very beginning.”

Human embryos are prized by medical researchers because of their fast and malleable regenerative properties. In theory, they could be used to heal severed spines, as well as damaged or diseased brains, hearts and other organs.

But their use is one of the most controversial issues in medical research, a controversy that centers on whether embryonic cell groupings, called blastocysts, are considered human life.

Dave Prentice, senior fellow for life sciences at the Christian organization Family Research Council, opposes the use of human embryos in research. “You shouldn’t be destroying human embryos at the earlier stage of human life to harvest cells,” said Prentice, who has a PhD. in biochemistry from the University of Kansas.

Other stem cell options are available, he said, such as harvesting them from umbilical cord blood or adult tissue, or “reprogramming” adult cells to behave like stem cells, as demonstrated in recently-released but early-stage studies.

Zoloth said she supports stem cell research because “the human embryo does not have the moral status of a dying child.” Like other supporters, she pointed to the vast potential – though still unproven – of this science in healing traumatic injuries and degenerative diseases.

“I strongly support learning as much as we possibly can about human embryonic stem cells, as well as learning about other types of regenerative medicines,” she said. “The fact that science could develop ways of healing very tragic human fates is an extraordinary capacity that we have been given by God. For people who aren’t religious, you might say that we stand in a remarkable moment in human history.”

Safety over ethics for the FDA

The FDA seems to be more concerned with the stem cells’ possible side effect of producing tumors. Because of the “potential risks” of human embryonic stem cell products, data showing a drug’s effectiveness “may need to be particularly strong,” the document said.

An administration spokesman would not comment further than the released document.

“The FDA needs to feel comfortable that the cells we use for our cell products will not cause teratomas,” said Alan Lewis, chief executive of privately-held biotech Novocell, which hopes to begin human stem cell testing within three years for a possible diabetes treatment.

Lewis described the teratomas as non-malignant but unwanted pieces of muscle, hair or other matter that form as an offshoot of embryonic stem cells, which replicate quickly and can morph into different types of tissues, such as the liver or pancreas.

The biotechs line up

Geron (GERN) could be the first company to conduct experiments in humans with drugs made from human embryonic stem cells. The biotech is developing a treatment to repair spinal cord injuries. Geron has already filed an application to the FDA to begin human testing, according to analysts. But the biotech refused to confirm this and would not discuss the upcoming meeting.

So far, Geron’s animal experiments have been tumor-free, said UBS analyst Graig Suvannavejh, who doesn’t expect the company to run into problems with the FDA.

“For Geron, the best possible outcome overall is for [the] FDA to be peachy with everything they’ve done so far,” said Suvannavejh in an email to CNNMoney.com. He believes Geron could begin human testing by mid-2008.

Steve Brozak, analyst for WBB Securities, emphasized that tumor-safety is imperative, and there is little room for failure in the current environment.

“It is one of the things that can be a problem if the science is not understood completely,” he said. Geron needs “to make sure that the critics of the field don’t have room to assail them with.”

Advanced Cell Technology is using embryonic stem cells to develop a treatment for vision loss. Chief scientific officer Robert Lanza said his company plans to file an application for human testing to the FDA within months. He said the company has found a way to “differentiate” stem cells to reduce the possibility of tumor formation.

Neuralstem (CUR) works with stem cells derived from a donated human fetus, rather than embryonic stem cells. CEO Richard Garr said his company is developing a treatment for Lou Gehrig’s disease, which degrades spinal cord nerve cells. He intends to file an application for human testing to the FDA in September or October.

Garr said that his company’s pig tests have been tumor-free, and he hopes the FDA panelists focus on the science of stem cells, not the controversy, in designing requirements for clinical trials.

“What we hope to come out of this meeting is rationality,” said Garr. “[We] hope that this isn’t just something that a stem cell-unfriendly administration is trying put in place before they leave.”

Research being presented April11 at the UK National Stem Cell Network Annual Science Meeting in Edinburgh could offer hope that bone stem cells may be harnessed to repair the damaged cartilage that is one of the main symptoms of osteoarthritis.

Scientists at Cardiff University have successfully identified stem cells within articular cartilage of adults, which although it cannot become any cell in the body like full stem cells, has the ability to derive into chondrocytes – the cells that make up the body’s cartilage — in high enough numbers to make treatment a realistic possibility. The team have even been able to identify the cells in people over 75 years of age.

Osteoarthritis affects over 2M people in the UK and occurs when changes in the make up of the body’s cartilage causes joints to fail to work properly. At its worse it can cause the break up of cartilage, causing the ends of the bones in the joint to rub against each other. This results in severe pain and deformation of the joint. One current treatment to treat damaged cartilage due to trauma in younger patients is to harvest cartilage cells from neighbouring healthy cartilage and transplant them into the damaged area. Unfortunately, only a limited number of cells can be generated.

The research team, funded by the Arthritis Research Campaign and the Swiss AO Foundation, have identified a progenitor, or a partially derived stem cell in bovine cartilage that can be turned into can be turned into a chondrocyte in culture. Their breakthrough came in identifying a similar cell in human cartilage that was more like a stem cell with characteristics that they could be used to treat cartilage lesions due to trauma but also mark the onset of osteoarthritis

Lead researcher Professor Charlie Archer from the Cardiff School of Biosciences said: “We have identified a cell which when grown in the lab can produce enough of a person’s own cartilage that it could be effectively transplanted. There are limitations in trying to transplant a patient’s existing cartilage cells but by culturing it from a resident stem cell we believe we can overcome this limitation.

“This research could have real benefits for arthritis sufferers and especially younger active patients with cartilage lesions that can progress to whole scale osteoarthritis.”

Prof Archer commented: “We have embarked on the next stage which is to conduct and animal trial which is a necessary pre-requisite to a clinical trial which we hope to start next year if the results are positive”

A unique partnership between industry and academia has led to human clinical trials of a new drug for a rare class of blood diseases called myeloproliferative disorders (MPD), which are all driven by the same genetic mutation and can evolve into leukemia. In just one year, collaborative discoveries by stem cell researchers from the University of California, San Diego, Dana-Farber Cancer Institute, the Mayo Clinic and a San Diego pharmaceutical company, TargeGen, moved from identification of the most promising drug candidate to clinical trials for a new drug to fight this degenerative blood disorder, which affects more than 100,000 Americans.

A study headed by Catriona H.M. Jamieson, M.D. Ph.D., assistant professor of medicine at the University of California, San Diego and Director for Stem Cell Research at Moores UCSD Cancer Center, found an inhibitor that can stop the over-proliferation of blood cells that results in problems with blood clotting, heart attacks and, in some cases, leukemia. Funded in part by a grant from the California Institute for Regenerative Medicine (CIRM), the study will be published in Cancer Cell on April 8, 2008. A parallel study at Harvard Medical School, headed by D. Gary Gilliland, Ph.D., M.D., yielded similar results which will appear in the same issue of Cancer Cell.

“As a clinician, I asked myself who is going to get this disease, and what can we do to stop its progression, instead of waiting until it evolves into a deadly cancer?” said Jamieson. “This project has been so extraordinary, because a small pharmaceutical company took a big chance on a rare disease.”

With major contributions from collaborators Jason Gotlib at Stanford University and Ayalew Tefferi at the Mayo Clinic, the research findings led to development of the inhibitor by TargeGen. That drug is currently being tested in human clinical trials at the UC San Diego School of Medicine, the Mayo Clinic, M.D. Anderson Cancer Center, and the University of Michigan, Stanford and Harvard University Schools of Medicine.

A patient with MPD makes too many blood cells, caused by a mutation expressed in the stem cell, the early stage cell that goes on to differentiate to become either red or white blood cells. In 2006, Jamieson was first author on a paper published in PNAS, outlining the discovery that a mutation in the JAK2 signaling pathway in patients with a type of MPD called polycythemia vera (PV) allows cells to bypass the process which would normally regulate the production of red blood cells. As a result of this defect, the bone marrow produces excessive numbers of red blood cells.

In the current research described in Cancer Cell, the UCSD School of Medicine researchers and collaborators transferred human cord blood stem cells, engineered to contain the mutant JAK2 gene, into mouse models with a suppressed immune system to find whether over-expression of a single gene could drive, or initiate, the disease. These stem cells were introduced directly into the liver, the main site of blood development in the newborn mouse. As a result, the stem cells over-expressing the mutant gene led to overproduction of human red blood cells, and the mice developed a disease that looked like PV.

The researchers corroborated these results by injecting actual stem cells from patients with PV into the same mouse model, achieving similar results. “We found that the JAK2 mutation was necessary and sufficient, by itself, to drive the disease,” Jamieson said.

Theorizing that blocking this mutation would prevent overproduction of red blood cells, TargeGen developed a selective JAK2 inhibitor called TG101348. This therapy was shown in animal studies to halt over-expression of the gene and reverse excessive production of red blood cells. Because TG101348 selectively targets the JAK2 protein that causes the disease, side effects have been minimized.

“Pre-clinical testing at the UCSD and Harvard University Schools of Medicine confirmed the therapeutic potential of TG101348. The compound was rapidly advanced into the current, ongoing human clinical trials being conducted at major research institutions across the country,” said John Hood, Ph.D., Director of Research for TargeGen. “This unique industry-academia collaboration has helped guide a new drug from bench to bedside, from evaluating the compound’s efficacy on cancer stem cells to its evaluation in patients bearing a disease which otherwise has very limited treatment options.”

Under the auspices of Jamieson, co-first authors Ifat Geron, M.S., and Annelie Abrahamsson, M.S., worked in close collaboration with Kenneth Kaushansky, M.D., chair of the UCSD Department of Medicine; Jason Gotlib, M.D., M.S., at Stanford University School of Medicine; and Ayalew Tefferi, M.D., Department of Medicine at the Mayo Clinic in Minnesota.

Additional contributors to this study include Charlene Barroga, Ph.D. and Edward Kavalerchik, M.D., UCSD Department of Medicine; John Hood, Ph.D., Chi Ching Mak, Glenn Noronha and Richard Soll, Ph.D., TargeGen Inc., San Diego; and Jeffrey Durocher, PH.D., Transgenomic Inc., Gaithersberg, MD. The study was funded in part by the California Institute for Regenerative Medicine and the Mizrahi Family Foundation, the National Institutes of Health (K23HL04409) and an unrestricted gift from TargeGen Inc.

Adapted from materials provided by University of California – San Diego, via EurekAlert!, a service of AAAS.