Human skin tissue, genetically reprogrammed into human-induced pluripotent stem cells (hiPSCs) , was able to inject the cells into rat hearts and get new heart tissue integrated to the rat hearts.
For the first time scientists have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells that are capable of integrating with existing heart tissue.
The research, which is published online today (Wednesday) in the European Heart Journal , opens up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. As the reprogrammed cells would be derived from the patients themselves, this could avoid the problem of the patients' immune systems rejecting the cells as "foreign". However, the researchers warn that there are a number of obstacles to overcome before it would be possible to use hiPSCs in humans in this way, and it could take at least five to ten years before clinical trials could start.
I think we need a legal environment that allows a more aggressive approach to human trials. For someone within 5 years of dying from heart failure the risks (notably cancer) of therapy using hiPSC should be weighed against otherwise inevitable death from heart failure.
The stem cells were derived from older patients with heart disease. This demonstrates a patient's own cells could be reprogrammed to restore damaged tissue.
Recent advances in stem cell biology and tissue engineering have enabled researchers to consider ways of restoring and repairing damaged heart muscle with new cells, but a major problem has been the lack of good sources of human heart muscle cells and the problem of rejection by the immune system. Recent studies have shown that it is possible to derive hiPSCs from young and healthy people and that these are capable of transforming into heart cells. However, it has not been shown that hiPSCs could be obtained from elderly and diseased patients. In addition, until now researchers have not been able to show that heart cells created from hiPSCs could integrate with existing heart tissue.
The danger is that the reprogrammed cells will become cancerous. But if you otherwise have but a few years left to live you should be allowed to throw the dice and try a stem cell therapy.
Ms Limor Zwi-Dantsis, who is a PhD student in the Sohnis Research Laboratory, Prof Gepstein and their colleagues took skin cells from two male heart failure patients (aged 51 and 61) and reprogrammed them by delivering three genes or "transcription factors" (Sox2, Klf4 and Oct4), followed by a small molecule called valproic acid, to the cell nucleus. Crucially, this reprogramming cocktail did not include a transcription factor called c-Myc, which has been used for creating stem cells but which is a known cancer-causing gene.
"One of the obstacles to using hiPSCs clinically in humans is the potential for the cells to develop out of control and become tumours," explained Prof Gepstein. "This potential risk may stem from several reasons, including the oncogenic factor c-Myc, and the random integration into the cell's DNA of the virus that is used to carry the transcription factors – a process known as insertional oncogenesis.
The researchers think we are still 5-10 years away from clinical trials of this approach. I think shows how the regulatory and legal environment causes an excessively conservative and slow approach to development of revolutionary therapies.
If we only knew how to instruct cells to do exactly what we want then most human degeneration with age would become repairable. Some Yale researchers have found a way to block an inhibitor mechanism so that new arteries grow in mice and zebrafish.
"Successfully growing new arteries could provide a biological option for patients facing bypass surgery," said lead author of the study Michael Simons, M.D., chief of the Section of Cardiology at Yale School of Medicine.
In the past, researchers used growth factors—proteins that stimulate the growth of cells—to grow new arteries, but this method was unsuccessful. Simons and his team studied mice and zebrafish to see if they could simulate arterial formation by switching on and off two signaling pathways—ERK1/2 and P13K.
"We found that there is a cross-talk between the two signaling pathways. One half of the signaling pathway inhibits the other. When we inhibit this mechanism, we are able to grow arteries," said Simons. "Instead of using growth factors, we stopped the inhibitor mechanism by using a drug that targets a particular enzyme called P13-kinase inhibitor."
"Because we've located this inhibitory pathway, it opens the possibility of developing a new class of medication to grow new arteries," Simons added. "The next step is to test this finding in a human clinical trial."
Drugs that block this inhibitor pathway could be problematic since they might cause artery growth in many parts of the body. We need techniques that allow localized control of cell growth. It isn't enough to have stem cells. Therapeutic techniques must control cell organization in 3 dimensions to grow the needed structures.
CHICAGO --- The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer deaths than those who didn't receive stem cells.
In the 12-month Phase II, double-blind trial, subjects' own purified stem cells, called CD34+ cells, were injected into their hearts in an effort to spur the growth of small blood vessels that make up the microcirculation of the heart muscle. Researchers believe the loss of these blood vessels contributes to the pain of chronic, severe angina.
"This is the first study to show significant benefit in pain reduction and improved exercise capacity in this population with very advanced heart disease," said principal investigator Douglas Losordo, M.D., the Eileen M. Foell Professor of Heart Research at the Northwestern University Feinberg School of Medicine and a cardiologist and director of the program in cardiovascular regenerative medicine at Northwestern Memorial Hospital, the lead site of the study.
I looki\ forward to seeing lots of stem cell therapies move into clinical use. Stem cells will displace long term drug use for many problems because the stem cells will be able to repair and not just manage a problem.
Researchers, led by principal investigator Zhongjie Sun, tested the effect of an anti-aging gene called klotho on reducing hypertension. They found that by increasing the expression of the gene in laboratory models, they not only stopped blood pressure from continuing to rise, but succeeded in lowering it. Perhaps most impressive was the complete reversal of kidney damage, which is associated with prolonged high blood pressure and often leads to kidney failure.
“One single injection of the klotho gene can reduce hypertension for at least 12 weeks and possibly longer. Klotho is also available as a protein and, conceivably, we could ingest it as a powder much like we do with protein drinks,” said Sun, M.D., Ph.D., a cardiovascular expert at the OU College of Medicine.
Would this work for humans?
The decline in klotho protein seen with age might play a contributing role with rising hypertension and kidney damage.
Scientists have been working with the klotho gene and its link to aging since 1997 when it was discovered by Japanese scientists. This is the first study showing that a decline in klotho protein level may be involved in the progression of hypertension and kidney damage, Sun said. With age, the klotho level decreases while the prevalence of hypertension increases.
A lot of problems with age seem to come in cascades. In this case the level of a protein goes down causing hypertension which in turn damages the kidneys. Lots of other cascades of failure are building up in all of use. We need the biotechnologies which can stop and reverse these cascades of failure.
ROCHESTER, Minn. -- Mayo Clinic investigators have demonstrated that stem cells can be used to regenerate heart tissue to treat dilated cardiomyopathy, a congenital defect. Publication of the discovery was expedited by the editors of Stem Cells and appeared online in the "express" section of the journal's Web site at http://stemcells.alphamedpress.org/.
And yet people do not complain that mice get all the great medical treatments first. Why is that? My theory: the mice have somehow brainwashed us. PETA (People for the Ethical Treatment of Animals) are really a secret organization of people who are immune to mouse brainwashing. They pose as animal rights activists. But in reality they are human rights activists trying to move humans ahead of mice in priority for treatment development. If the mice find out that I've told you this then I'll probably have to get some cats as bodyguards.
The key here is that the scientists used embryonic stem cells. This seems pretty straightforward to try in humans except for the regulatory obstacles that stand in the way.
The team reproduced prominent features of human malignant heart failure in a series of genetically altered mice. Specifically, the "knockout" of a critical heart-protective protein known as the KATP channel compromised heart contractions and caused ventricular dilation or heart enlargement. The condition, including poor survival, is typical of patients with heritable dilated cardiomyopathy.
Researchers transplanted 200,000 embryonic stem cells into the wall of the left ventricle of the knockout mice. After one month the treatment improved heart performance, synchronized electrical impulses and stopped heart deterioration, ultimately saving the animal's life. Stem cells had grafted into the heart and formed new cardiac tissue. Additionally, the stem cell transplantation restarted cell cycle activity and halved the fibrosis that had been developing after the initial damage. Stem cell therapy also increased stamina and removed fluid buildup in the body, so characteristic in heart failure.
Embryonic stem cells are pluripotent. That means they can become all other cell types. Another way to create pluripotent stem cells without using an embryo will eventually make it possible to create pluripotent stem cells that do not raise big ethical opposition.
The use of stem cells to do repairs will be easier for some organs than others. I'm hopeful from reports like the one above that most heart problems will be among the easier problems to solve.
Looking ahead 20 years I'm most worried about cancer and brain aging. I would be surprised if organ failures will still kill a lot of people in industrialized countries 20 years from now. Will cancer become easily curable in 20 years? Maybe. But brain aging is going to be the hardest problem to solve.
Heart rejuvenation is fundamentally a DNA programming problem. With enough knowledge about how to run the DNA software we can make stem cells become replacement cells in cardiac muscle and in the rest of the body.
SAN FRANCISCO, CA –March 5, 2008--Researchers at the Gladstone Institute of Cardiovascular Disease (GICD) and the University of California, San Francisco have identified for the first time how tiny genetic factors called microRNAs may influence the differentiation of pluripotent embryonic stem (ES) cells into cardiac muscle. As reported in the journal Cell Stem Cell, scientists in the lab of GICD Director, Deepak Srivastava, MD, demonstrated that two microRNAs, miR-1 and miR-133, which have been associated with muscle development, not only encourage heart muscle formation, but also actively suppress genes that could turn the ES cells into undesired cells like neurons or bone.
“Understanding how pluripotent stem cells can be used in therapy requires that we understand the myriad processes and factors that influence cell fate,” said Dr. Srivastava. “This work shows that microRNAs can function both in directing how ES cells change into specific cells—as well as preventing these cells from developing into unwanted cell types.”
These microRNAs trigger gene activity that turns the embryonic stem cells into cardiac muscle. With more knowledge about the activity of hundreds (or perhaps thousands) of microRNAs we will be able to make large numbers of tissue types from stem cells. It is a matter of discovering a large number of possible ways to instruct cells to do our bidding.
How long will it take to figure which microRNA can tell which cell type to become which other cell type? I'm thinking that microfluidics will speed up this process by automating the testing of large numbers of microRNAs with large numbers of cell types. The rate of advance in stem cell manipulation will accelerate every year as microfluidic devices and other tools for lab automation allow the solution space to be searched orders of magnitude more rapidly.