Cleveland Clinic, December 17, 2008 — A multi-disciplinary team of doctors and surgeons at Cleveland Clinic recently performed the first near-total face transplant in the United States.
In a 22-hour procedure performed within the past two weeks, surgeons transplanted 80 percent of a woman’s face who suffered severe facial trauma – essentially replacing her entire face, except for her upper eyelids, forehead, lower lip and chin. For the privacy and protection of those involved, no information will be released on the patient, the donor, or their families.
This is the largest and most complex face transplant in the world, integrating different functional components such as nose and lower eyelids, as well as different tissue types including , skin, muscles, bony structures, arteries veins and nerves.
“This work demonstrates the Clinic’s commitment to improving the lives of patients through innovation,” said Delos M. “Toby” Cosgrove, M.D., President and CEO, Cleveland Clinic. “By advancing scientific research in microsurgery and transplantation, the Clinic is setting new standards of care. I’m extremely proud of the team of physicians and staff who worked tirelessly to make a difference in this patient’s life.”
The transplant team was led by Maria Siemionow, M.D., Ph.D., Section Head of Plastic Surgery Research, who received worldwide attention in November 2004 when the Clinic’s Institutional Review Board (IRB) announced that face transplantation is both ethical and possible by approving the first protocol for the surgery. Siemionow, a highly regarded scientist, has dedicated her professional life to researching and developing the methods doctors could use to substantially help patients with severe facial disfiguration.
The Cleveland Clinic Dermatology and Plastic Surgery Institute led the face transplant surgery, partnering with the Cleveland Clinic Head & Neck Institute. Staff members from psychology/psychiatry, bioethics, social work, anesthesia, transplant, nursing, infectious disease, dentistry, ophthalmology, pharmacy, environmental services and security were also significantly involved.
For more information, please call Cleveland Clinic at 1.888.428.2247 or 216-636-8535. Members of the media can call the Media Relations Department at 216.444.0141.
What is a mature stem cell?
Stem cells are associated with most tissues of the body as part of a tissue/cell renewal mechanism — how the body regenerates its tissues. What is known to date is that mature stem cells are primarily multipotent, meaning they can yield all of the cell types associated with the tissues from which they originate. The mature stem cell is an undifferentiated (unspecialized) cell that is found in a differentiated (specialized) tissue, which can renew itself for a lifetime.
What is the role of mature stem cells?
Mature stem cells maintain and repair the body’s tissues in which they are found.
Can mature stem cells become any type of body cell?
Traditionally, mature stem cells have been considered limited in their potential to become any type of body cell. In other words, they only produce cell varieties within their own lineage or type and are considered multipotent. For example, stem cells found in bone marrow can become bone as well as cartilage, fat cells, various kinds of muscle, and the cells that line blood vessels.
Can mature stem cells be pluripotent?
Unlike early stem cells, there is no evidence to date that any mature stem cells are capable of forming all cells of the body. However, recent studies have demonstrated that mature stem cells may be more flexible than previously thought. More studies are necessary to validate these results.
Where can mature stem cells be found?
Sources of mature stem cells have been found in areas of the body including bone marrow, blood stream, cornea and retina of the eye, the dental pulp of the tooth, liver, skin, gastrointestinal tract, and pancreas.
What is the most common type of mature stem cell used today?
The mature stem cells associated with those that form blood in bone marrow are the most common type of stem cell used to treat human diseases today.
How do mature stem cells treat diseases like cancer?
For more than 30 years, bone marrow stem cells have been used to treat cancer patients with conditions like leukemia and lymphoma. During chemotherapy, most of the leukemia cells are killed as are the bone marrow stem cells needed as a patient recovers. However, if stem cells are removed before chemotherapy, and then re-injected after treatment is completed, the stem cells in the bone marrow are able to produce large amounts of red and white blood cells, to keep the body healthy and to help fight infections.
FAQS about the Armed Forces Institute of Regenerative Medicine
What is the Armed Forces Institute of Regenerative Medicine?
The Armed Forces Institute of Regenerative Medicine (AFIRM) is a multi-institutional, interdisciplinary network working to develop advanced treatment options for our severely wounded servicemen and women. The AFIRM is managed and funded through the US Army Medical Research and Materiel Command (MRMC), with additional funding from the US Navy, the US Air Force, the National Institutes of Health, the Veterans Administration, and local public and private matching funding.
Which institutions make up the AFIRM?
The AFIRM is made up of two civilian research consortiums working with the US Army Institute of Surgical Research (USAISR) in Fort Sam Houston, Texas. One consortium is led by Rutgers, the State University of New Jersey and the Cleveland Clinic and one is led by Wake Forest University and The McGowan Institute in Pittsburgh. Each of these civilian consortia is itself a multi-institutional network. Click here for a full list of the institutions.
How much funding is allocated to the AFIRM?
Each of the civilian consortiums was awarded $42.5 million over a period of five years. In addition, the two consortia are bringing local public and private matching funds amounting to more than $80 million that will be added to their research budgets. In each case, the full amount of the grant was allocated to the lead institution. Those lead institutions are responsible for distributing the funds among their consortium partners according to peer-reviewed work plans that address the AFIRM therapeutic objectives.
How were the AFIRM Consortia chosen?
The process for awarding the AFIRM grants began in January 2007, with a Request for Information from the US Army MRMC. Twenty-eight institutions responded to this RFI. In April 2007, a draft Request for Proposal (RFP) was sent to those 28 respondents for comment. In August 2007, a Program Announcement was released by the Army MRMC. Seven consortia responded to this PA. From those, two finalists were chosen for oral presentations to the Scientific Review Panel in December 2007. Ultimately, both finalists were deemed to have built excellent programs and both were recommended for funding.
When does the AFIRM program start?
Much of the research activity to be funded by the AFIRM is already underway at the individual participating institutions. MRMC has issued cooperative agreements with the lead institution for each consortium and work will be starting during spring and summer 2008.
What sorts of therapies will be developed within the AFIRM?
The AFIRM was designed to speed the delivery of regenerative medicine therapies to treat our most critically injured servicemembers from around the world, but in particular those coming from our theaters of operation in Iraq and Afghanistan. There are five major programs: Limb Repair, Craniofacial Repair, Burn Repair, Scarless Wound Repair, and Compartment Syndrome Repair.
Regenerative Medicine? Does that mean stem cells?
Adult stem cells and progenitors are an integral part of normal wound healing and the formation of all new tissues. Many of the strategies being developed by AFIRM seek to improve wound healing and tissue repair by increasing the number or improving the function of adult stem cells. A patient’s own cells, or in some cases, cells from another adult, are used in conjunction with special drugs called bioactive factors, or with advanced biomaterials that serve as scaffolds for growth of new tissues.
Will AFIRM researchers be using embryonic stem cells?
No. All of the research now funded through the AFIRM will use adult-derived stem cells taken from the patient or from another consenting adult.
Can these stem cells regenerate entire arms and legs?
No; not at present. However, the use of these cells, bioactive factors and biomaterials can help injured servicemembers to optimize their own capacity to heal and recover by forming new bone, skin, nerves, tendons, muscles, and blood vessels to replace damaged tissues. AFIRM collaborators plan to use these new strategies to dramatically speed and enhance the outcome of tissue repair, leading to greater opportunity and a more effective return to productive life after injury.
What are tissue scaffolds?
Tissue scaffolds are the medical implants of the future: small, porous, tissue-like implants made of fully degradable, specially designed biomaterials that support cells at the site of injury and assist the body in growing new, functional tissue. When the damaged or lost tissue has been successfully replaced by new tissue, the scaffold will have completely resorbed. Examples are regeneration of damaged or missing sections of bones, nerves, ligaments, blood vessels and skin.
Are companies participating in the AFIRM?
Dozens of commercial interests have expressed a willingness to work with the AFIRM consortia as commercialization partners. We are extremely pleased that the American medical device industry has taken such a keen interest in speeding these important new therapies to market not just for injured service members, but for civilian patients as well. We believe that this participation will ultimately lead to better healthcare options for all Americans.
Participating AFIRM Institutions
USA ISR Core
• The US Army Institute of Surgical Research, Ft. Sam Houston, TX
• Brooke Army Medical Center, Ft. Sam Houston, TX
RCC Consortium (led by Rutgers and the Cleveland Clinic)
• Rutgers, The State University of New Jersey
• Cleveland Clinic
• Carnegie Mellon University
• Case Western Reserve University/University Hospitals Case Medical Center
• Dartmouth Hitchcock Medical Center
• Massachusetts General Hospital/Harvard Medical School
• Massachusetts Institute of Technology
• Mayo Clinic
• Northwestern University
• Stony Brook University
• University of Cincinnati
• University of Medicine and Dentistry of New Jersey
• University of Pennsylvania
• University of Virginia
• Vanderbilt University
WFM Consortium (led by Wake Forest University and the McGowan Institute)
• Wake Forest Institute for Regenerative Medicine, Wake Forest University
• Baptist Medical Center
• McGowan Institute for Regenerative Medicine, University of Pittsburgh
• Allegheny Singer Research Institute
• California Institute of Technology
• Carnegie Mellon University
• Georgia Institute of Technology
• Oregon Medical Laser Center at Providence St. Vincent Medical Center
• Pittsburgh Tissue Engineering Initiative
• Rice University
• Stanford University School of Medicine
• Tufts University
• University of California, Santa Barbara
• University of Texas Health Science Center at Houston
• University of Wisconsin
• Vanderbilt University
Armed Forces Institute for Regenerative Medicine: The Rutgers-Cleveland Cllinic AFIRM Team
Joachim Kohn, Ph.D.
Rutgers, the State University of New Jersey, Piscataway, New Jersey
· Director of New Jersey Center for Biomaterials
· Board of Governors Professor, Department of Chemistry and Chemical Biology
· Adjunct Associate Professor of Orthopedics at the New Jersey Medical School
George F. Muschler, MD
Cleveland Clinic, Cleveland, Ohio
· Staff Surgeon, Department of Orthopaedic Surgery
· Director, Orthopaedic Research Center and the Clinical Tissue Engineering Center
· Vice-Chairman, Department of Biomedical Engineering
· Vice-Chairman for Research, Orthopedic and Rheumatologic Institute
Daniel G. Anderson, PhD
Massachusetts Institute of Technology, Cambridge, Massachusetts
· Research Associate, David H. Koch Institute for Integrative Cancer Research
Steven T. Boyce, PhD
University of Cincinnati, Cincinnati, Ohio
· Professor, Dept of Surgery, College of Medicine
· Adjunct Professor, Dept of Biomedical Engineering, College of Engineering
· Senior Investigator, Research Department Shriners Burns Hospital, Cincinnati, Ohio
Arnold I. Caplan, Ph.D.
Case Western Reserve University, Cleveland, Ohio
· Director, Skeletal Research Center
· Professor, Departments of Biology; General Medical Sciences (Oncology); Pathology and Biomedical Engineering
Richard A Clark, MD
Stony Brook University, Stony Brook, New York
· Director, Center of Tissue Engineering
· Professor, Department of Biomedical Engineering, Dermatology
· Adjunct Professor, Department of Medicine
Kathleen A. Derwin, Ph.D.
Cleveland Clinic, Cleveland, Ohio
· Assistant Staff, Department of Biomedical Engineering, Lerner Research Institute, and Joint Appointee, Department of Orthopaedic Surgery
· Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
· Adjunct Assistant Professor, Department of Biomedical Engineering, Case Western Reserve University
· Adjunct Faculty, Department of Chemical and Biomedical Engineering, Cleveland State University
David Devore, PhD
Rutgers, the State University of New Jersey, Piscataway, New Jersey
· Chief Operating Officer, Center for Military Biomaterials Research (CeMBR)
· Associate Research Professor Department of Chemistry and Chemical Biology
Paul Ducheyne, PhD
University of Pennsylvania, Philadelphia, PA
· Professor of Bioengineering, Orthopaedic Surgery Research
· Director of Center for Bioactive Materials and Tissue Engineering
· Member, Institute for Medicine and Engineering
Michael G. Dunn, PhD
UMDNJ – Robert Wood Johnson Medical School, New Brunswick, New Jersey
· Associate Professor of Orthopaedic Surgery and Founding Director, Orthopaedic Research Laboratories
· Faculty Member, Rutgers-UMDNJ Joint Graduate Program in Biomedical Engineering
Charles J. Gatt, MD
UMDNJ Robert Wood Johnson Medical School, New Brunswick, New Jersey
· Chairman, Department of Orthopaedic Surgery,
· Adjunct Faculty, School of Biomedical Engineering, Rutgers University, New Brunswick, New Jersey
Stanton Gerson, M.D
University Hospitals Case Medical Center, Cleveland, Ohio
· Asa and Patricia Shiverick Professor
· Director of the Case Comprehensive Cancer Center and Ireland Cancer Center
· Director of the Ohio Wright Center for Stem Cell and Regenerative Medicine at Case School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio
Linda Griffith, Ph.D.
Massachusetts Institute of Technology, Cambridge, Massachusetts
· Director of MIT Biotech/Pharma Engineering Center
· School of Engineering Teaching Innovation Professor
· Department of Biological Engineering and Department of Mechanical Engineering
Scott A. Guelcher, PhD
Vanderbilt University, Nashville, Tennessee
· Assistant Professor, Department of Chemical Engineering
Jeffrey O. Hollinger, DDS, PhD
Carnegie Mellon University, Pittsburgh, Pennsylvania
· Director, Bone Tissue Engineering Center
· Professor, Biomedical Engineering Department
Adam J. Katz, MD
University of Virginia
· Associate Professor of Plastic and Reconstructive Surgery, University of Virginia Health System
· Adjunct Associate Professor of Medicine
· Director, Chronic Wound Care Clinic
· Director, Laboratory of Applied Developmental Plasticity
Robert S. Langer , ScD
Massachusetts Institute of Technology, Cambridge, Massachusetts
· Germeshausen Professor of Chemical and Biomedical Engineering, Department of Chemical Engineering
Thomas A. Mustoe, MD
Northwestern University, Evanston, Illinois
· Professor and Chief, Division of Plastic Surgery
· Feinberg School of Medicine Professor
· Director of Wound Healing Research Laboratory
Joseph M. Rosen, MD
Dartmouth-Hitchcock Medical Center
· Professor of Surgery, Division of Plastic Surgery
· Adjunct Associate Professor and Senior Lecturer, Thayer School of Engineering at Dartmouth
· Chair of IED Task Force Medical Sub-Panel, Defense Science Board
Maria Z. Siemionow, MD, PhD, DSc
Cleveland Clinic, Cleveland, Ohio
· Director, Plastic Surgery Research, Department of Plastic Surgery
· Head, Microsurgery Training, Microsurgery Laboratory of the Department of Plastic Surgery
· Professor of Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Adam J. Singer, MD
Stony Brook University, Stony Brook, New York
· Vice Chairman of Research and Professor, Department of Emergency Medicine
Cleveland Clinic, Cleveland, Ohio
· Executive Director, Clinical Tissue Engineering Center, Cleveland Clinic and State of Ohio Department of Development, Cleveland, OH
· Commercialization Manager, Cleveland Clinic Innovations
Cathryn Sundback, Sc.D.
Massachusetts General Hospital, Cambridge, Massachusetts
· Director of the Laboratory for Tissue Engineering and Organ Fabrication
Joseph P. Vacanti, MD
Harvard Medical School
· John Homans Professor of Surgery
· Chief, Department of Pediatric Surgery, Massachusetts General Hospital (MGH)
· Surgeon-in-Chief, MGH Hospital for Children
· Co-Director, Center for Regenerative Medicine, MGH
· Director, Laboratory for Tissue Engineering and Organ Fabrication, MGH
· Chief, Pediatric Transplantation, MGH
Michael J. Yaszemski, M.D., Ph.D.
Mayo Clinic, Rochester, Minnesota
· Professor of Orthopedics and Biomedical Engineering
· Director, Tissue Engineering and Biomaterials Laboratory
Stem cells harvested from young women’s menstrual blood have a longer lifespan than those from older women
ScienceDaily.com — Researchers seeking new and more abundant sources of stem cells for use in regenerative medicine have identified a potentially unlimited, noncontroversial, easily collectable, and inexpensive source — menstrual blood.
Stromal stem cells – cells that are present in connective tissues – have recently been identified in endometrial tissues of the uterus. When the fresh growth of tissue and blood vessels is shed during each menstrual cycle, some cells with regenerative capabilities are present and collectable. While collecting menstrual blood stromal cells (MenSCs) directly from tissue would be invasive, retrieving them during the menstrual cycle would not be.
“Stromal stem cells derived from menstrual blood exhibit stem cell properties, such as the capacity for self-renewal and multipotency,” said Amit N. Patel, MD, MS, Director of Cardiac Cell Therapy at the University of Pittsburgh’s McGowan Institute of Regenerative Medicine. “Uterine stromal cells have similar multipotent markers found in bone marrow stem cells and originate in part from bone marrow.”
These menstrual stem cells could offer several advantages. They come from a source that’s easy to obtain from women, they could be used to treat patients without the fear of tissue rejection, and they avoid the ethical questions associated with embryonic stem cells.
Published in the most recent issue of Cell Transplantation (Volume 17, issue 3), the study examined to what degree MenSCs demonstrated an ability to differentiate into a variety of cell lineages.
Tests showed that MenSCs could differentiate into adipogenic, chondrogenic, osteogenic, ectodermal, mesodermal, cardiogenic, and neural cell lineages. According to Patel, the sample MenSCs expanded rapidly and maintained greater than 50 percent of their telomerase activity when compared to human embryonic stem cells and better than bone marrow-derived stem cells. “Studies have demonstrated that MenSCs are easily expandable to clinical relevance and express multipotent markers at both the molecular and cellular level,” concluded Patel.
Researchers emphasized the importance of the abundance and plasticity of MenSCs. Based on the results of their studies, they noted the potential for MenSCs in regenerative transplantation therapies for many different organs and tissues. “The need for regenerative therapies using cells with the ability to engraft and differentiate is vast,” said Patel.
“The ideal cell would also have the ability to be used in an allogenic manner from donors for optimal immunogenic compatibility. Due to their ease of collection and isolation, MenSCs would be a great source of multipotent cells if they exhibit this property along with their ability to differentiate,” concluded Julie G. Allickson, Ph.D., Vice President of Laboratory Operations and Research & Development, Cryo-Cell International, Inc., the study-partner company that identified, extracted, and initially analyzed the cells. “The preliminary results are extremely encouraging and support the importance of further study of these cells in several different areas including heart disease, diabetes and neurodegenerative disease.”
Dwaine Emerich, Ph.D., a section editor for Cell Transplantation, believes that “These studies are a significant step forward in the development of transplantable stem cells for human diseases because they address major issues including routine and safe cell harvesting of renewable cells that maintain their differentiation capacity and can be scaled for widespread clinical use.”
MediStem Laboratories, San Diego, CA
Stem cells derived from human menstrual blood have, in mice, prevented limbs with restricted blood flow from withering. Trials in humans facing amputations are expected to start in 2009..
Last November, scientists working for MediStem Laboratories, in San Diego, California, announced that they had discovered adult stem cells within the menstrual blood collected from two women. They claimed the cells were shed from the endometrium, which lines the uterus and has to be rebuilt every month.
Now Thomas Ichim, of MediStem, and his team have published a proof-of-principle study in mice, showing that the endometrial stem cells revitalise damaged limbs in much the same way that bone-marrow-derived stem cells do.
The researchers induced “critical limb ischaemia” (which is damagingly low blood flow) in the legs of 16 healthy mice. Immediately after, then again on days 2 and 4, the researchers injected half of the animals with 1 million endometrial stem cells in the hind-limb muscle, just below the injury. By day 14, tissue in the legs of the control mice had begun to die. The limbs of the treated mice, by contrast, were all alive, although two of them had some difficulty walking.
The finding suggests, say the authors, that endometrial stem cells can stimulate blood-vessel growth. Endometrial stem cells appear not to provoke an immune reaction, opening the possibility of developing an “off the shelf” cell population.
Some 150,000 people in the US lose limbs to critical limb ischaemia every year, and there is no cure. Ichim hopes to begin trials in this patient population sometime next year. “These are people who are going to get their legs amputated,” he says.
/PRNewswire-FirstCall/ — Cryo-Cell International, Inc. announced results of a study published in Cell Transplantation showing that stem cells found in menstrual blood proliferate rapidly and have significant potential to develop into multiple cell types. Menstrual stem cells offer an easily accessible, non-controversial and renewable stem cell source, and these findings could mean these cells have the potential to one day treat a host of diseases.
The study, “Multipotent Menstrual Blood Stromal Stem Cells: Isolation, Characterization and Differentiation,” was conducted by researchers at Cryo- Cell International who originally discovered the stem cells. According to the study, the stem cells in menstrual blood, known as MenSCs, are stromal stem cells, meaning they have the capability to differentiate into important cells, such as such as bone, cartilage, fat, nerve and cardiogenic cells. The study also found that the cells divided rapidly and plentifully, indicating a possible therapeutic value.
With additional studies of the cells in a variety of categories, the use of these cells may lead to treatments for a number of serious diseases, such as osteoporosis, stroke, Alzheimer’s and Parkinson’s disease. The cells may even one day be used for customized anti-aging or sports medicine treatments.
“These findings demonstrate that this novel cell population is adequately potent to one day be a routinely and safely isolated source of stem cells,” said Julie Allickson, Ph.D., study investigator and Vice President, Laboratory Operations, Research and Development at Cryo-Cell International, Inc. “Clinical trials are now underway to test the safety and efficacy of MenSCs in animal models for diabetes, neurodegenerative and cardiovascular regenerative therapies.”
“As we research several sources of stem cells for their potential therapeutic benefits, we look for cells to emulate embryonic stem cells in that they have the ability to grow rapidly and to become many different types of cells,” said Dr. Camillo Ricordi, director of the Cell Transplant Center and the Diabetes Research Institute at the University of Miami. “These menstrual stem cells could have several of the embryonic stem cell attributes, in addition to being easily extracted, not controversial and renewable.”
During the study, the investigators analyzed shed menstrual blood and tissue to identify MenSCs. The samples were obtained using a menstrual cup and transferred to a laboratory for processing. At the lab, the cells were quality control-tested and grown in culture to allow for expansion and to assess their growth capabilities. Further analyses were conducted to assess the cells’ ability to differentiate into new cell lines, in order to determine which diseases the cells may be used to treat. The average cell collection from a sample of menstrual blood was approximately five million, of which 75 percent of the cells were considered viable. Importantly, the cells rapidly expanded at a doubling rate of 24-36 hours, starting with 50,000 cells on day one and culminating into 48 million cells in less than one month.
“This promising study is the first of many we are conducting in collaboration with leading researchers and institutions with the ultimate goal of using these stem cells to develop groundbreaking future treatments,” said Mercedes Walton, Cryo-Cell’s Chairman and CEO. “These initial findings offer scientific support and validation for women who are interested in preserving their own menstrual blood stem cells for potential future benefit.”
Based on the results of the study, Cryo-Cell is pursuing further research into menstrual stem cells. Cryo-Cell is organizing a number of research and development agreements in efforts to develop promising regenerative therapies utilizing C’elle technology in cardiology, diabetes and neurological diseases. Results from these studies are expected in the next year. The Company is actively seeking to expand its portfolio of research collaborations with scientists worldwide interested in studying this novel stem cell population for regenerative therapeutic development. Cryo-Cell’s C’elle(SM) service, which was introduced in November, 2007, is the first available product that enables women to collect menstrual flow containing stem cells, which can then be cryogenically preserved in a manner similar to stem cells from umbilical cord blood.
About Cryo-Cell International, Inc. (OTC Bulletin Board: CCEL.OB)
Based in Oldsmar, Florida, with over 150,000 clients worldwide, Cryo-Cell is one of the largest and most established family cord blood banks. ISO 9001: 2000 certified and accredited by the AABB, Cryo-Cell operates in a state-of- the-art Good Manufacturing Practice and Good Tissue Practice (cGMP/cGTP)- compliant facility. Cryo-Cell is a publicly traded company. OTC Bulletin Board Symbol: CCEL. For more information, please call 1-800-STOR-CELL (1-800- 786-7235) or visit http://www.cryo-cell.com.
Japanese Scientists at the American College of Cardiology
Japanese researchers have harvested stem cells from human menstrual blood, a medical conference has heard.
The researchers say these stem cells could be coaxed into forming specialised heart cells, which might one-day be used to treat failing or damaged hearts.
At the meeting of the American College of Cardiology, Dr Shunichiro Miyoshi reported that he and his colleagues at Keio University in Tokyo collected menstrual blood from six women and harvested stem cells that originated in the lining of the uterus.
They were able to obtain about 30 times more stem cells from menstrual blood than from bone marrow, Miyoshi says.
The stem cells were then cultured in a way to induce them to become heart cells.
After five days about half of the cells contracted “spontaneously, rhythmical and synchronously, suggesting the presence of electrical communication” between the cells, Miyoshi says.
That is to say, they behaved like heart cells.
The researcher explains that already stem cells derived from bone marrow have improved heart function, mainly by producing new blood vessels rather than new heart-muscle tissue.
He emphasises that it is important that these cells be obtained from younger patients, because they would have a longer lifespan than cells harvested from older donors.
Muscle Stem Cells
Photo: Douglas Cowan, Children’s Hospital Boston.
Young Blood Revives Aging Muscles
Stanford Univ School of Medicine — Any older person can attest that aging muscles don’t heal like young ones. But it turns out that’s not the muscle’s fault. A study published in Nature shows that it’s old blood that keeps the muscles down.
The study, led by Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences at the Stanford University School of medicine, built on previous work showing that old muscles have the capacity to repair themselves but fail to do so. Rando and his group studied specialized cells called satellite cells, the muscle stem cells, that dot muscle tissue. These normally lie dormant but come to the rescue in response to damaged muscle-at least they do in young mice and humans.
In older mice the satellite cells hold the same position, but are deaf to the muscle’s cry for help. In the Nature study, Rando and his group first attached old mice to their younger lab-mates in a way that caused the two mice to share a blood supply. They then induced muscle damage only in the older mice. Bathed in the presence of younger blood, the old muscles healed normally. In contrast, when old mice were connected to other old mice they healed slowly.
In similar work, the group examined the livers of older mice connected to younger lab-mates. The cells that help liver tissue regenerate are less active in older animals, but again the cells responded more robustly when the livers in older mice were bathed in the younger blood. Clearly, something in the youthful blood revived the regenerative cells in muscle and liver.
“We need to consider the possibility that the niche in which stem cells sit is as important in terms of stem cell aging as the cells themselves,” said Rando, who is also an investigator at the Veterans Affairs Palo Alto Health Care System. It could be the chemical soup surrounding the cells, not the cells themselves, that’s at fault in aging.
One clue to what might be going on also comes from previous work. Rando had found that satellite cells in younger muscles begin producing a protein dubbed Delta in response to muscle damage. Older muscles maintained the same pre-injury levels of Delta even after muscle damage. However, in the current study he found that satellite cells in elderly mice joined to younger partners ramped up Delta production to youthful levels after an injury.
The group confirmed their results by putting satellite cells from old and young mice in a lab dish with either old or young blood serum. Old satellite cells in old serum and young satellite cells in young serum both behaved as expected. But when old satellite cells were bathed in young serum they cranked up their production of Delta and began dividing. Likewise, young satellite cells decreased the amount of Delta they produced when in a dish with older serum and divided less frequently.
Rando said that it may be a general phenomenon that a person’s inability to repair tissues with age-whether it’s muscle, liver, skin or brain-is a matter of the regenerative cell’s environment rather than the cells themselves.
Rando said that finding the youth-promoting factors in the blood is no small task. “It’s as big a fishing expedition as you can possibly imagine,” he said. With thousands of proteins, lipids, sugars and other small molecules in the blood serum, deciding where to look first would be tantamount to a roll of the dice. What’s more, there’s no evidence that the same blood component is responsible for reviving the different types of cells.
“Another approach is to pick factors that are good candidates and see if any of them or some combination recapitulate the effect of the younger blood,” Rando said. His group is now looking for likely targets. He said that for some degenerative diseases such as Alzheimer’s or muscular dystrophy, such blood-borne factors may be able to reactivate the regenerative cell’s ability to repair tissue that has been damaged.
Regenerative Medicine & The National Institutes of Health(NIH)
Can Stem Cells Repair a Damaged Heart?
Stem Cell Research
Heart attacks and congestive heart failure remain among the Nation’s most prominent health challenges despite many breakthroughs in cardiovascular medicine. In fact, despite successful approaches to prevent or limit cardiovascular disease, the restoration of function to the damaged heart remains a formidable challenge. Recent research is providing early evidence that adult and embryonic stem cells may be able to replace damaged heart muscle cells and establish new blood vessels to supply them. Discussed here are some of the recent discoveries that feature stem cell replacement and muscle regeneration strategies for repairing the damaged heart.
For those suffering from common, but deadly, heart diseases, stem cell biology represents a new medical frontier. Researchers are working toward using stem cells to replace damaged heart cells and literally restore cardiac function.
Today in the United States, congestive heart failure—the ineffective pumping of the heart caused by the loss or dysfunction of heart muscle cells—afflicts 4.8 million people, with 400,000 new cases each year. One of the major contributors to the development of this condition is a heart attack, known medically as a myocardial infarction, which occurs in nearly 1.1 million Americans each year. It is easy to recognize that impairments of the heart and circulatory system represent a major cause of death and disability in the United States.
What leads to these devastating effects? The destruction of heart muscle cells, known as cardiomyocytes, can be the result of hypertension, chronic insufficiency in the blood supply to the heart muscle caused by coronary artery disease, or a heart attack, the sudden closing of a blood vessel supplying oxygen to the heart. Despite advances in surgical procedures, mechanical assistance devices, drug therapy, and organ transplantation, more than half of patients with congestive heart failure die within five years of initial diagnosis. Research has shown that therapies such as clot-busting medications can reestablish blood flow to the damaged regions of the heart and limit the death of cardiomyocytes. Researchers are now exploring ways to save additional lives by using replacement cells for dead or impaired cells so that the weakened heart muscle can regain its pumping power.
How might stem cells play a part in repairing the heart? To answer this question, researchers are building their knowledge base about how stem cells are directed to become specialized cells. One important type of cell that can be developed is the cardiomyocyte, the heart muscle cell that contracts to eject the blood out of the heart’s main pumping chamber (the ventricle). Two other cell types are important to a properly functioning heart are the vascular endothelial cell, which forms the inner lining of new blood vessels, and the smooth muscle cell, which forms the wall of blood vessels. The heart has a large demand for blood flow, and these specialized cells are important for developing a new network of arteries to bring nutrients and oxygen to the cardiomyocytes after a heart has been damaged. The potential capability of both embryonic and adult stem cells to develop into these cells types in the damaged heart is now being explored as part of a strategy to restore heart function to people who have had heart attacks or have congestive heart failure. It is important that work with stem cells is not confused with recent reports that human cardiac myocytes may undergo cell division after myocardial infarction. This work suggests that injured heart cells can shift from a quiescent state into active cell division. This is not different from the ability of a host of other cells in the body that begin to divide after injury. There is still no evidence that there are true stem cells in the heart which can proliferate and differentiate.
Researchers now know that under highly specific growth conditions in laboratory culture dishes, stem cells can be coaxed into developing as new cardiomyocytes and vascular endothelial cells. Scientists are interested in exploiting this ability to provide replacement tissue for the damaged heart. This approach has immense advantages over heart transplant, particularly in light of the paucity of donor hearts available to meet current transplantation needs.
What is the evidence that such an approach to restoring cardiac function might work? In the research laboratory, investigators often use a mouse or rat model of a heart attack to study new therapies. To create a heart attack in a mouse or rat, a ligature is placed around a major blood vessel serving the heart muscle, thereby depriving the cardiomyocytes of their oxygen and nutrient supplies. During the past year, researchers using such models have made several key discoveries that kindled interest in the application of adult stem cells to heart muscle repair in animal models of heart disease.
Figure 9.1. Rodent Model of Myocardial Infarction.
Recently, Orlic and colleagues reported on an experimental application of hematopoietic stem cells for the regeneration of the tissues in the heart. In this study, a heart attack was induced in mice by tying off a major blood vessel, the left main coronary artery. Through the identification of unique cellular surface markers, the investigators then isolated a select group of adult primitive bone marrow cells with a high capacity to develop into cells of multiple types. When injected into the damaged wall of the ventricle, these cells led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells, thus generating de novo myocardium, including coronary arteries, arterioles, and capillaries. The newly formed myocardium occupied 68 percent of the damaged portion of the ventricle nine days after the bone marrow cells were transplanted, in effect replacing the dead myocardium with living, functioning tissue. The researchers found that mice that received the transplanted cells survived in greater numbers than mice with heart attacks that did not receive the mouse stem cells. Follow-up experiments are now being conducted to extend the posttransplantation analysis time to determine the longer-range effects of such therapy. The partial repair of the damaged heart muscle suggests that the transplanted mouse hematopoietic stem cells responded to signals in the environment near the injured myocardium. The cells migrated to the damaged region of the ventricle, where they multiplied and became “specialized” cells that appeared to be cardiomyocytes.
A second study, by Jackson et al., demonstrated that cardiac tissue can be regenerated in the mouse heart attack model through the introduction of adult stem cells from mouse bone marrow. In this model, investigators purified a “side population” of hematopoietic stem cells from a genetically altered mouse strain. These cells were then transplanted into the marrow of lethally irradiated mice approximately 10 weeks before the recipient mice were subjected to heart attack via the tying off of a different major heart blood vessel, the left anterior descending (LAD) coronary artery. At two to four weeks after the induced cardiac injury, the survival rate was 26 percent. As with the study by Orlic et al., analysis of the region surrounding the damaged tissue in surviving mice showed the presence of donor-derived cardiomyocytes and endothelial cells. Thus, the mouse hematopoietic stem cells transplanted into the bone marrow had responded to signals in the injured heart, migrated to the border region of the damaged area, and differentiated into several types of tissue needed for cardiac repair. This study suggests that mouse hematopoietic stem cells may be delivered to the heart through bone marrow transplantation as well as through direct injection into the cardiac tissue, thus providing another possible therapeutic strategy for regenerating injured cardiac tissue.
More evidence for potential stem cell-based therapies for heart disease is provided by a study that showed that human adult stem cells taken from the bone marrow are capable of giving rise to vascular endothelial cells when transplanted into rats. As in the Jackson study, these researchers induced a heart attack by tying off the LAD coronary artery. They took great care to identify a population of human hematopoietic stem cells that give rise to new blood vessels. These stem cells demonstrate plasticity meaning that they become cell types that they would not normally be. The cells were used to form new blood vessels in the damaged area of the rats’ hearts and to encourage proliferation of preexisting vasculature following the experimental heart attack.
Like the mouse stem cells, these human hematopoietic stem cells can be induced under the appropriate culture conditions to differentiate into numerous tissue types, including cardiac muscle. When injected into the bloodstream leading to the damaged rat heart, these cells prevented the death of hypertrophied or thickened but otherwise viable myocardial cells and reduced progressive formation of collagen fibers and scars. Control rats that underwent surgery with an intact LAD coronary artery, as well as LAD-ligated rats injected with saline or control cells, did not demonstrate an increase in the number of blood vessels. Furthermore, the hematopoietic cells could be identified on the basis of highly specific cell markers that differentiate them from cardiomyocyte precursor cells, enabling the cells to be used alone or in conjunction with myocyte-regeneration strategies or pharmacological therapies.
Figure 9.2. Heart Muscle Repair with Adult Stem Cells
Exciting new advances in cardiomyocyte regeneration are being made in human embryonic stem cell research. Because of their ability to differentiate into any cell type in the adult body, embryonic stem cells are another possible source population for cardiac-repair cells. The first step in this application was taken by Itskovitz-Eldor et al. who demonstrated that human embryonic stem cells can reproducibly differentiate in culture into embryoid bodies made up of cell types from the body’s three embryonic germ layers. Among the various cell types noted were cells that had the physical appearance of cardiomyocytes, showed cellular markers consistent with heart cells, and demonstrated contractile activity similar to cardiomyocytes when observed under the microscope.
In a continuation of this early work, Kehat et al. displayed structural and functional properties of early stage cardiomyocytes in the cells that develop from the embryoid bodies. The cells that have spontaneously contracting activity are positively identified by using markers with antibodies to myosin heavy chain, alpha-actinin, desmin, antinaturietic protein, and cardiac troponin—all proteins found in heart tissue. These investigators have done genetic analysis of these cells and found that the transcription-factor genes expressed are consistent with early stage cardiomyocytes. Electrical recordings from these cells, changes in calcium-ion movement within the cells, and contractile responsiveness to catecholamine hormone stimulation by the cells were similar to the recordings, changes, and responsiveness seen in early cardiomyocytes observed during mammalian development. A next step in this research is to see whether the experimental evidence of improvement in outcome from heart attack in rodents can be reproduced using embryonic stem cells.
These breakthrough discoveries in rodent models present new opportunities for using stem cells to repair damaged heart muscle. The results of the studies discussed above are growing evidence that adult stem cells may develop into more cell types than first thought. In those studies, hematopoietic stem cells appear to be able to develop not only into blood, but also into cardiac muscle and endothelial tissue. This capacity of adult stem cells, increasingly referred to as “plasticity,” may make such adult stem cells a viable candidate for heart repair. But this evidence is not complete; the mouse hematopoietic stem cell populations that give rise to these replacement cells are not homogenous. Rather, they are enriched for the cells of interest through specific and selective stimulating factors that promote cell growth. Thus, the originating cell population for these injected cells has not been identified, and the possibility exists for inclusion of other cell populations that could cause the recipient to reject the transplanted cells. This is a major issue to contend with in clinical applications, but it is not as relevant in the experimental models described here because the rodents have been bred to be genetically similar.
What are the implications for extending the research on differentiated growth of replacement tissues for damaged hearts? There are some practical aspects of producing a sufficient number of cells for clinical application. The repair of one damaged human heart would likely require millions of cells. The unique capacity for embryonic stem cells to replicate in culture may give them an advantage over adult stem cells by providing large numbers of replacement cells in tissue culture for transplantation purposes. Given the current state of the science, it is unclear how adult stem cells could be used to generate sufficient heart muscle outside the body to meet patients’ demand .
Although there is much excitement because researchers now know that adult and embryonic stem cells can repair damaged heart tissue, many questions remain to be answered before clinical applications can be made. For example, how long will the replacement cells continue to function? Do the rodent research models accurately reflect human heart conditions and transplantation responses? Do these new replacement cardiomyocytes derived from stem cells have the electrical-signal-conducting capabilities of native cardiac muscle cells?
Stem cells may well serve as the foundation upon which a future form of “cellular therapy” is constructed. In the current animal models, the time between the injury to the heart and the application of stem cells affects the degree to which regeneration takes place, and this has real implications for the patient who is rushed unprepared to the emergency room in the wake of a heart attack. In the future, could the patient’s cells be harvested and expanded for use in an efficient manner? Alternatively, can at-risk patients donate their cells in advance, thus minimizing the preparation necessary for the cells’ administration? Moreover, can these stem cells be genetically “programmed” to migrate directly to the site of injury and to synthesize immediately the heart proteins necessary for the regeneration process? Investigators are currently using stem cells from all sources to address these questions, thus providing a promising future for therapies for repairing or replacing the damaged heart and addressing the Nation’s leading causes of death.
RESBIO is an NIH-funded national biomedical technology resource that fosters multidisciplinary investigations, integrating chemical, biological and materials research with the goal of supplying biomedical engineers with the biomaterials and devices that will enable new kinds of therapies.
One of RESBIO’s key research goals is to contribute to a better understanding of cellular interactions with tissue scaffolds.
Step 1: Engineered Cells express GFP-labeled markers to allow the direct imaging of key cellular responses when grown on tissue scaffolds in vitro.
Example: Saos-2 cells expressing GFP-fusions with actin, actinin, paxillin, and RhoA are visualized with multi-photon laser scanning microscopy to show important details of the cellular interaction with the underlying substratum.
Step 2: Changes in scaffold architecture can now be explored in detail.
Example: Exploration of cell ular adhesion on electrospun po lymer fibers as a function of the fiber diameter. Saos-2/pGFP-actin cells reveal that if the fiber diameter is relatively large (left), the cell’s actin stress fibers will predominantly align with the polymer fibers, while at small fiber diameters (right), the cell will regard the fiber scaffold essentially as a “patterned surface” and the actin stress fibers do not align with the polymer fibers.
One of RESBIO’s key technology goals is to develop a computational approach to accelerate biomaterials discovery.
Step 1: Rapid parallel synthesis of polymer libraries and the development of rapid screening assays to explore the property profiles of biomaterials.
Parallel Synthesis Robot
Rapid Screening Assays
Step 2: Development computational tools for rapid screening of potential candidates forr novel poymeric biomaterials.
Using state-of-the-art computational approaches including molecular dynamic simulations combined with docking and datamining, new polymeric biomaterials are developed. This prescreening approach of large polymer libraries helps in development of interesting “lead” biomaterials as drug delivery systems, implants etc, reducing the time and cost efforts as part of rational design process.
Innovative biomaterials-based therapies and medical devices.
Example 1: Collaboration on partially degradable hernia-repair device.
TyRx Pharma looked for a polymer suitable for development of a drug-eluting hernia repair device. A degradable polymer with optimal properties was identified in RESBIO’s combinatorially designed library of polyarylates.
FDA clearance for marketing was obtained via a 510(k) application process within 90 days of submission of the application. The device under the trade name “PivitTM” entered clinical use in June 2006.
Example 2: Radio-opaque cardiovascular stent made of a degradable polymer.
RESBIO’s combinatorial synthesis of new polymers and its computational models played a key role in the discovery of fundamentally new polymer compositions that were specifically optimized for use in radio-opaque, fully resorbable cardiovascular stents. With in 2 years, this work has progressed to the point that “first-in-man” studies are expected in the near future.
RESBIO is supported by funding from the National Institute
of Biomedical Imaging and Bioengineering, National Institutes of Health
A man in Scotland calls his son in London the day before Christmas Eve and says, “I hate to ruin your day, but I have to tell you that your mother and I are divorcing; forty-five years of misery is enough.”
“Dad, what are you talking about?” the son screams.
“We can’t stand the sight of each other any longer,” the father says.
“We’re sick of each other, and I’m sick of talking about this, so you call
your sister in Leeds and tell her.”
Frantic, the son calls his sister, who explodes on the phone. “Like hell
they’re getting divorced,” she shouts, “I’ll take care of this.”
She calls Scotland immediately, and screams at her father, “You are NOT
getting divorced. Don’t do a single thing until I get there. I’m calling my
brother back, and we’ll both be there tomorrow. Until then, don’t do a
Thing, DO YOU HEAR ME?” and hangs up.
The old man hangs up his phone and turns to his wife. “Okay,” he says,
“they’re coming for Christmas and they’re paying their own way.”