BERLIN, December 15, 2008 — Up until today scientists assumed that the adult heart is unable to regenerate. Now, researchers and cardiologists from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and the Charité – Universitätsmedizin Berlin (Germany) have been able to show that this dogma no longer holds true.
Dr. Laura Zelarayán and Assistant Professor Dr. Martin W. Bergmann were able to show that the body`s own heart muscle stem cells do generate new tissue and improve the pumping function of the heart considerably in an adult organism, when they suppress the activity of a gene regulator known as beta-catenin in the nucleus of the heart cells.*
The gene regulator beta-catenin plays an important role in the development of the heart in embyros. Dr. Zelarayán and Dr. Bergmann could now show that beta-catenin is also important for the regeneration of the adult heart. They suppressed this factor in the nucleus of the heart cells in mice.
This way they activated heart precursor cells (stem cells) to turn on the regeneration of heart in adult mice. Four weeks after blocking beta-catenin, the pumping function of the heart of the animals had improved and the mice survived an infarction much better than those animals with a functioning beta-catenin gene. An important contribution to this project has been a transgenic mouse line generated by Professor Walter Birchmeier`s (MDC) laboratory.
Markers identified for Heart Muscle Stem Cells
In addition, the researchers have proven that heart muscle stem cells exist. So far, these cells had not been characterized clearly. They could demonstrate that two markers for heart cells – the structural protein alpha myosin heavy chain and the transcriptionfactor Tbx5 – are also expressed on heart precursor cells. “The evidence of cells with these markers in the adult heart demonstrates that stem cells dating back from heart development survive in niches in the adult heart”, Dr. Bergmann explains.
The researchers in Germany collaborated with scientists in the Netherlands and Belgium. For this research, Dr. Bergmann was awarded the Wilhelm P. Wintersteinpreis this summer. The research group of Dr. Bergmann, a guest researcher at the MDC who recently became Deputy of the Department of Cardiology at the Asklepios Clinic St. Georg in Hamburg, belongs to the research group of Professor Rainer Dietz (MDC and Charité).
*Beta-catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation.
1. Laura Zelarayán et al. Beta-Catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation. PNAS, Online December 10, 2008 DOI: 10.1073/pnas.0808393105
Adapted from materials provided by Helmholtz Association of German Research Centres
Heart Derived Stem Cells Develop Into Heart Muscle
Utrecht, 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.
Anatomy and Function of the Coronary Arteries
Coronary arteries supply blood to the heart muscle. Like all other tissues in the body, the heart muscle needs oxygen-rich blood to function, and oxygen-depleted blood must be carried away. The coronary arteries consist of two main arteries: the right and left coronary arteries, and their two branches, the circumflex artery and the left anterior descending artery.
What are the different coronary arteries?
The two main coronary arteries are the left and right coronary arteries. The left coronary artery (LCA), which divides into the left anterior descending artery and the circumflex branch, supplies blood to the heart ventricles and left atrium. The right coronary artery (RCA), which divides into the right posterior descending artery and a large marginal branch, supplies blood to the heart ventricles, right atrium, and sinoatrial node (cluster of cells in the right atrial wall that regulates the heart’s rhythmic rate).
Additional arteries branch off the two main coronary arteries to supply the heart muscle with blood. These include the following:
· circumflex artery (Cx)
The circumflex artery branches off the left coronary artery and encircles the heart muscle. This artery supplies blood to the back of the heart.
· left anterior descending artery (LAD)
The left anterior descending artery branches off the left coronary artery and supplies blood to the front of the heart.
Smaller branches of the coronary arteries include: acute marginal, posterior descending (PDA), obtuse marginal (OM), and diagonals.
Why are the coronary arteries important?
Since coronary arteries deliver blood to the heart muscle, any coronary artery disorder or disease can have serious implications by reducing the flow of oxygen and nutrients to the heart, which may lead to a heart attack and possibly death. Atherosclerosis (a build-up of plaque in the inner lining of an artery causing it to narrow or become blocked) is the most common form of coronary artery disease.
Restoring youth: Older muscles typically grow new cells slower than young ones do, but inhibiting a key pathway in the stem cells of aging mice appears to restore youthful vigor. In these two images, muscle stem cells are shown in red, and muscle fibers in green. The top image, which shows muscle from older mice given the inhibitory treatment, clearly exhibits more muscle growth than the bottom one, which shows muscle from untreated aging mice.
Credit: UC Berkley
Researchers boost growth of muscle stem cells to stop age-related muscle deterioration.
By Jennifer Chu
Manipulating stem cells in old muscle can restore youth to aging tissue, according to research from the University of California, Berkeley. Scientists altered the activity of a molecular pathway to make stem cells in older tissue produce new muscle fibers at levels comparable to young stem cells. They say that their findings may one day lead to novel therapies for age-related diseases such as Alzheimer’s and Parkinson’s, as well as possibly to the reversal of the atrophying effect of aging.
“When we exert ourselves, like going to the gym or running after the bus, we always damage muscles which are being replaced over time [by] muscle stem cells,” says Irina Conboy, assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center. “But when we get older, cell death is faster than cell replacement.”
Muscle wasting–loss of muscle mass–occurs both during aging and in a number of diseases, such as cancer and muscular dystrophy. Because muscle loss often correlates with poor health outcomes, pharmaceutical companies have been striving to find new treatments that boost muscle mass without the harmful side effects of anabolic steroids.
In previous research, Conboy’s team found that old stem cells, placed in culture with young blood and muscle tissue, were able to churn out new cells at a speedier rate. Conversely, young stem cells exposed to old tissue grew prematurely old, significantly scaling back new-cell production. Conboy reasoned that stem cells must receive different chemical cues in youth versus in old age, and identifying and manipulating those cues may successfully restore youth to old muscle.
In their current study, published in the online edition of the journal Nature, Conboy and her team found that old muscle produces elevated levels of a molecule called TGF-beta, which is known to inhibit muscle growth. The researchers then showed that the muscle-deteriorating effects of TGF-beta can be reversed by blocking its pathway in old mice.
In the experiments, the researchers used RNA interference, which can silence specific genes, to inhibit the molecules that act downstream of TGF-beta to prevent cells from multiplying. They then locally injured the muscles of treated mice, as well as untreated old and young mice, by injecting a small amount of snake venom, which killed muscle tissue in the immediate vicinity.
After five days, the team found that the young mice were able to produce healthy cells to replace damaged tissue. The treated older mice, whose inhibitory pathways were suppressed, were able to regenerate new cells in much the same way. Not surprisingly, old untreated mice did not recover as well and developed fibroblasts and scar tissue around the injured site.
Conboy says that regulating the TGF-beta pathway may provide a therapeutic possibility for treating age-related muscle disorders. However, she adds that shutting down the pathway altogether may lead to unwanted consequences, such as tumor growth and other side effects. She says that the team’s next goal is to find an appropriate balance between TGF-beta activity and another protein, called Notch, which has previously been shown to successfully rejuvenate old tissue.
Both proteins bind to the same receptors on the surface of stem cells and therefore naturally compete with each other. “In physiologically young animals, Notch is high and TGF-beta is low, and in old animals, it’s the opposite,” says Conboy. “These levels are definitely regulated by the aging process, but we don’t yet know what is the cause.”
Conboy says that this relationship reflects an unfortunate cycle in aging: as levels of Notch drop off with age, TGF-beta is left with ample room to inhibit stem cells, further suppressing the body’s ability to repair damaged tissue. “It’s a self-imposed inhibition of regeneration,” says Conboy.
Michael Rudnicki, director of the Regenerative Medicine Program and the Sprott Centre for Stem Cell Research at the Ottawa Health Research Institute, says that while finding appropriate calibrations may prove challenging, identifying the relationship between Notch and TGF-beta pathways may be a first step in developing therapies for a range of diseases.
Notch and TGF-beta are present in the stem cells of other organs, including the brain, so a similar approach may be a way of repairing tissue in these other organs. “One can think about targets for drug development to reverse or ameliorate many phenomena,” says Rudnicki. “Whether it will reverse aging, I don’t know, but it would be helpful for soft tissue damage or following a stroke.”
Dr. Michael Sacks Named 2009 Recipient of the ASME Van C. Mow Medal
McGowan Institute for Regenerative Medicine faculty member Michael Sacks, PhD, the William Kepler Whiteford Professor, Department of Bioengineering, University of Pittsburgh, has been named the 2009 recipient of the American Society of Mechanical Engineers (ASME) Van C. Mow Medal. Dr. Sacks was selected to receive this prestigious honor for his contributions in
McGowan Institute faculty member Dr. Michael Sacksadvancing biomechanics of native and engineered heart valve tissues. The Van C. Mow Medal, established in 2004, is bestowed upon an individual who has demonstrated meritorious contributions to the field of bioengineering through research, education, professional development, leadership in the development of the profession, mentorship to young bioengineers, and with service to the bioengineering community.
Congratulations, Dr. Sacks!
Vol. 453, No. 7193 pp 301–351
The capacity of most tissues to regenerate derives from stem cells, but there are many barriers to the use of stem-cell-based therapies in the clinic. Such therapies, however, have the potential to improve human health enormously, and knowledge gained from studying cells in culture and in model organisms is now laying the groundwork for a new era of regenerative medicine.
Nature, by Natalie DeWitt — Life is regenerative, by definition. But by and large, humans lack the regenerative capacity of creatures such as newts and hydra. Although some of our cells have the innate ability to replenish themselves — and, by doing so, to repair ageing and injured tissues and organs — most of the body’s cells form the specialized cell type they are destined for and then go into lock down.
Having said that, humans do have organs and tissues, such as liver and skin, that regenerate well. Unfortunately, the insults of injury, disease and age wreak havoc on those that don’t. This explains why diseases of the heart, an organ famously recalcitrant to regeneration, are killers. And even organs than can regenerate eventually succumb to the ravages of ageing.
The field of reprogramming began with John Gurdon’s seminal work on the reprogramming of frog cells by cloning. His experiments showed that somatic cells that normally cannot regenerate (the majority of cells) can be stimulated to do so in certain circumstances. By bathing the nuclei of somatic cells in protein factors obtained from eggs, or even by inserting a few genes, the cells take on the quality of embryonic cells — the most regenerative cells of all.
Human musings on regeneration are ancient, as illustrated by the tale of the luckless Greek titan Prometheus. By day, an eagle torments him by tearing out his liver, only for the organ to regenerate overnight ready to be torn out again the next day. Now, scientists are discovering our bodies’ innate stem cells and how to create new sources of such cells in a Petri dish. This knowledge is transforming biology.
The articles in this Insight explore the promises and challenges of the next era of regenerative medicine — and how to use the information gained from the study of model organisms and cell culture to eventually heal ourselves. For an additional perspective, see Nature Reports Stem Cells (http://www.nature.com/stemcells/index.html) for a series of Q&As with the Insight authors.
1. Natalie DeWitt, Senior Editor
Nature 453, 302-305 (15 May 2008) | doi:10.1038/nature07037; Published online 14 May 2008
Regenerative medicine and human models of human disease
Kenneth R. Chien
Recent advances in stem-cell technology are now allowing the mechanisms of human disease to be studied in human cells. A new era for regenerative medicine is arising from such disease models, extending beyond early cell-based therapies and towards evaluating genetic variation in humans and identifying the molecular pathways that lead to disease, as well as targets for therapy.
1. Cardiovascular Research Center, Massachusetts General Hospital, Simches Research Center, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
2. Department of Stem Cell and Regenerative Biology, Harvard University, 42 Church Street, Cambridge, Massachusetts 02138, USA.
Nature 453, 314-321 (15 May 2008) | doi:10.1038/nature07039; Published online 14 May 2008
Wound repair and regeneration
Geoffrey C. Gurtner, Sabine Werner, Yann Barrandon & Michael T. Longaker
The repair of wounds is one of the most complex biological processes that occur during human life. After an injury, multiple biological pathways immediately become activated and are synchronized to respond. In human adults, the wound repair process commonly leads to a non-functioning mass of fibrotic tissue known as a scar. By contrast, early in gestation, injured fetal tissues can be completely recreated, without fibrosis, in a process resembling regeneration. Some organisms, however, retain the ability to regenerate tissue throughout adult life. Knowledge gained from studying such organisms might help to unlock latent regenerative pathways in humans, which would change medical practice as much as the introduction of antibiotics did in the twentieth century.
1. Division of Plastic and Reconstructive Surgery, Department of Surgery, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 257 Campus Drive, Stanford, California 94305-5148, USA.
2. Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology (ETH), Schafmattstrasse 18, HPM D42, CH-8093 Zürich, Switzerland.
3. Centre Hospitalier Universitaire Vaudois, Chirurgie Éxperimentale, Pavillon 4, CH-1011 Lausanne, Switzerland.
4. École Polytechnique Fédérale Lausanne, School of Life Sciences/LDCS, Station 15, CH-1015 Lausanne, Switzerland.
Nature 453, 322-329 (15 May 2008) | doi:10.1038/nature07040; Published online 14 May 2008
Stem-cell-based therapy and lessons from the heart
Robert Passier, Linda W. van Laake & Christine L. Mummery
The potential usefulness of human embryonic stem cells for therapy derives from their ability to form any cell in the body. This potential has been used to justify intensive research despite some ethical concerns. In parallel, scientists have searched for adult stem cells that can be used as an alternative to embryonic cells, and, for the heart at least, these efforts have led to promising results. However, most adult cardiomyocytes are unable to divide and form new cardiomyocytes and would therefore be unable to replace those lost as a result of disease. Basic questions — for example, whether cardiomyocyte replacement or alternatives, such as providing the damaged heart with new blood vessels or growth factors to activate resident stem cells, are the best approach — remain to be fully addressed. Despite this, preclinical studies on cardiomyocyte transplantation in animals and the first clinical trials with adult stem cells have recently been published with mixed results.
1. Hubrecht Institute, Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
2. Department of Anatomy and Embryology, Leiden University Medical Centre, Einthovenweg 20, 2333 Leiden, The Netherlands.
3. University Medical Center Utrecht, Division Heart and Lungs, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Nature 453, 338-344 (15 May 2008) | doi:10.1038/nature07042; Published online 14 May 2008
A chemical approach to stem-cell biology and regenerative medicine
Yue Xu1, Yan Shi1 & Sheng Ding1
An improved understanding of stem-cell and regenerative biology, as well as a better control of stem-cell fate, is likely to produce treatments for many devastating diseases and injuries. Chemical approaches are starting to have an increasingly important role in this young field. Attention has focused on chemical approaches that allow the precise manipulation of cells in vitro to obtain homogeneous cell types for cell-based therapies. Another promising approach is the development of conventional chemical and biological therapeutics to stimulate endogenous cells to regenerate. Such therapeutics can act on target cells or their niches in vivo to promote cell survival, proliferation, differentiation, reprogramming and homing.
1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature 453, 306-313 (15 May 2008) | doi:10.1038/nature07038; Published online 14 May 2008
Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal
Leonard I. Zon
When stem cells divide, they can generate progeny with the same developmental potential as the original cell, a process referred to as self-renewal. Self-renewal is driven intrinsically by gene expression in a cell-type-specific manner and is modulated through interactions with extrinsic cues from the environment, such as growth factors. However, despite the prevalence of the term self-renewal in the scientific literature, this process has not been defined at the molecular level. Haematopoietic stem cells are an excellent model for the study of self-renewal because they can be isolated prospectively, manipulated relatively easily and assessed by using well-defined assays. Establishing the principles of self-renewal in haematopoietic stem cells will lead to insights into the mechanisms of self-renewal in other tissues.
1. Stem Cell Program and Division of Hematology/Oncology, Children’s Hospital Boston, Karp 7, 1 Blackfan Circle, Boston, Massachusetts 02115, USA.
Nature 453, 330-337 (15 May 2008) | doi:10.1038/nature07041; Published online 14 May 2008
Tolerance strategies for stem-cell-based therapies
Ann P. Chidgey, Daniel Layton, Alan Trounson & Richard L. Boyd
There is much interest in using embryonic stem cells to regenerate tissues and organs. For this approach to succeed, these stem cells or their derivatives must engraft in patients over the long term. Unless a cell transplant is derived from the patient’s own cells, however, the cells will be targeted for rejection by the immune system. Although standard methods for suppressing the immune system achieve some success, rejection of the transplant is inevitable. Emerging approaches to address this issue include ‘re-educating’ the immune system to induce tolerance to foreign cells and reducing the immune targeting of the transplant by administering ‘self stem cells’ instead of foreign cells, but each of these approaches has associated challenges.
1. Monash Immunology and Stem Cell Laboratories, Building 75, STRIP, Monash University, Wellington Road, Clayton 3800, Victoria, Australia.
2. Present address: California Institute for Regenerative Medicine, 210 King Street, San Francisco, California 94107, USA.
Nature 453, 345-351 (15 May 2008) | doi:10.1038/nature07043; Published online 14 May 2008
Imaging stem-cell-driven regeneration in mammals
The ability to observe biological processes continuously, instead of at discrete time points, holds great promise for the study of tissue regeneration. Ideally, single cells would be followed continuously within large tissue volumes (such as organs) over long periods of time. Technical limitations, however, preclude such studies. But, recently, there have been improvements in imaging technologies and biologically compatible labelling agents. Together with new insights into the molecular characteristics of stem cells, which are ultimately responsible for the regenerative potential of all tissues, researchers are now much closer to applying single-cell imaging approaches to research into regeneration and its clinical applications.
1. Institute of Stem Cell Research, Helmholtz Zentrum München – German Research Center for Environmental Health, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.