McGowan Institute?
September 2007 | VOL. 6, NO. 9 | www.McGowan.pitt.edu
In a study using human muscle tissue, a team of scientists led by Bruno Péault, PhD and Johnny Huard, PhD isolated and characterized stem cells taken from blood vessels (known as myoendothelial cells) that are easily isolated using cell-sorting techniques, proliferate rapidly, and can be differentiated in the laboratory into muscle, bone and cartilage cells. These characteristics may make them ideally suited as a potential therapy for muscle injuries and diseases.
“Finding this population of stem cells in a human source represents a major breakthrough for us because it brings us much closer to a clinical application of this therapy,” said Dr. Huard, the Henry J. Mankin Professor and vice chair for Research in the Department of Orthopaedic Surgery at the University of Pittsburgh School of Medicine. “To make this available as a therapy, we would take a muscle biopsy from a patient with a muscle injury or disease, remove the myoendothelial cells, and treat the cells in the lab. The stem cells would then be re-injected into the patient to repair the muscle damage. Because this is an autologous transplant, meaning from the patient to himself, there is not the risk of rejection you would have if you took the stem cells from another source.”
Eight years ago, Dr. Huard’s laboratory team first identified a unique population of muscle-derived stem cells with the ability to repair muscle. Dr. Péault, a professor in the Department of Pediatrics, Cell Biology and Physiology at the University of Pittsburgh School of Medicine, recognized the importance of determining the origin of these muscle-derived stem cells. His team applied, among others, techniques of confocal microscopy and cell sorting by flow cytometry that led to the discovery in human muscle biopsies that these myoendothelial cells are located adjacent to the walls of blood vessels.
According to their study, myoendothelial cells taken from the blood vessels are much more efficient at forming muscle than other sources of stem cells known as satellite and endothelial cells. In mice, 1,000 myoendothelial cells transplanted into injured skeletal muscle produced, on average, 89 muscle fibers, compared with 9 and 5 muscle fibers for endothelial and satellite cells, respectively. Also, myoendothelial cells show no tendency to form tumors, a concern of other stem cell therapies.
Other authors in the study entitled, “Prospectivbe identification of myogenic endothelial cells in human skeletal muscle” include Bo Zheng, Baohong Cao, Mihaela Crisan, Bin Sun, Guangheng Li, Alison Logar, Solomon Yap, Jonathan B. Pollett, Lauren Drowley, Theresa Cassino, Burhan Gharaibeh, and Bridget M. Deasy. The recently published paper is also featured as our publication of the month this month. Read More
The work of the Badylak Lab is featured in the October issue of Esquire magazine in “A Doctor, a Pig, and a Magic Pixie Dust That Could Regrow Fingers.” The portrait of Dr. Badylak that emerges from the story closely follows his work with the submucosa of certain animal intestines being used as extracellular matrix. Since much of the research has been done using pig models, Esquire writer Michael Rosenwald made the origin and process of getting pigs from farm to lab part of the story and the title.
The magic pixie dust is, as anyone who has taken the standard McGowan Institute tour and watched the slides can tell you, the powder of ground-up pig bladder that was sprinkled on the severed tip of Lee Spievack’s finger when he amputated it with the propeller blade of a model airplane. Of course there is a happy ending, as foreshadowed by the fairy tale-like title of the story. After the finger was sprinkled every other day with the magic powder, the missing one-half inch tip of the finger actually regrew (regenerated) and is now a perfect facsimile of Spievack’s finger before the accident.
The Badylak Lab feature-length story was #3 in Esquire’s annual Top 100 list, taking top billing in the category of Medical Breakthrough of the Year. The magazine can be purchased at newsstands, and the story can also be accessed on-line.
PBS unveils a new series in October, Wired Science, a weekly look at science and technology as seen through the eyes of people who are leading the scientific advances. The Wired Science idea evolved from Wired magazine (known to be somewhat irreverent), although the TV series promotes itself as concentrating on solid narrative journalism.
The cast of the show along with the technical crew visited McGowan Institute in August to meet with key personnel here and to put together a feature on McGowan that will highlight studies related to tissue engineering and cellular therapy. Be sure to tune in on Wednesday, October 24, 2007 at 8:00 pm to WQED-TV locally to catch the segment that features McGowan Institute. PBS describes their ideal audience for this show as curious, engaged people that love PBS but want to see more science and technology.
George Mazariegos, MD, McGowan faculty member and director of pediatric transplantation at Children's Hospital at the University of Pittsburgh Medical Center, was recently interviewed and shared his insights on the half-liver transplant procedure. There have been several of these procedures recently done in Florida. Locally, Children’s Hospital has completed one.
As reported in an August press release from the Jackson (FL) Health System, a rare half-liver transplant was successfully performed on 2 year-old Brenner Logan in Holtz Children’s Hospital at the University of Miami/Jackson Memorial Hospital. The Florida child was released from the hospital 1 week after the transplant procedure. This is the same hospital where now 6-year-old Alexander Mongene underwent the same procedure two years ago.
In the operations, both boys were given only half a new liver. Half of their old liver was cut out, leaving the other half intact. The purpose of the new half liver, protected by anti-rejection drugs, is to take over the old liver’s function, easing the old liver’s load so it can regenerate. If the old liver grows back to its normal size, the anti-rejection drugs—which can have significant side effects—can be discontinued. Without these drugs, the new, transplanted half-liver will then wither away.
The half-liver transplant is new and somewhat controversial, experts say.
"I'd say it’s rare, with about 30 operations performed in Europe and only a handful in the United States," said Dr. Mazariegos, a leader in the field.
"There was initial enthusiasm in Europe, but then longer-term follow-up showed a higher rate of retransplantation than with full-liver transplants," he said. In Europe, doctors were urged to select candidates carefully for the surgery.
"You want a patient whose liver has a good chance of regeneration," said Mazariegos. "I'd say this is a good contribution, but the standard of care is still full-liver transplantation."
Children's Hospital of Pittsburgh has performed more than 1,000 pediatric liver transplants in children to date, making Children’s the most active pediatric liver transplant center in the country.
Satdarshan P. S. Monga, M.D., associate professor of pathology and medicine at the University of Pittsburgh School of Medicine, has been awarded $1.2 million by the National Cancer Institute to fund research into the role of beta-catenin in the development and growth of the most common form of liver cancer, hepatocellular cancer (HCC). Dr. Monga is also an Assistant Professor at the University of Pittsburgh Cancer Institute and a McGowan Institute faculty member.
Beta-catenin is a key protein in cellular interactions that is over-expressed in many cancers and thought to turn on genes involved in the development of HCC. Dr. Monga’s project, based on a mouse model, will focus on the biological mechanisms of tumor formation, specifically those related to beta-catenin.
According to Dr. Monga, the beta-catenin cell-signaling pathway is a very promising therapeutic target that may stop or slow the development of HCC in patients. Dr. Monga will use data gathered in the current study to examine the therapeutic effect of drugs proven to be safe in patients and known to inhibit this pathway, in preclinical models.
This latest grant comes on the heels of Dr. Monga’s recent publication regarding a targeted therapy for liver cancer using a newly available monoclonal antibody in a recent issue of Molecular Cancer Therapeutics and reported in the July issue of the McGowan Institute Newsletter.
Annually, the UPMC Heart, Lung and Esophageal Surgery Institute recognizes an individual who played an outstanding role in training and educating residents. For the 2006-2007 academic year, Kenton Zehr, MD, professor of surgery and chief, division of cardiac surgery at the University of Pittsburgh School of Medicine, was awarded the 2007 Cardiothoracic Surgical Faculty of the Year Award by the Institute.
In addition to a busy clinical practice, some of Dr. Zehr’s research interests include:
- A Phase II Randomized, Double-Blind Placebo-Controlled Study of the Effect of h5G1.1scFv of Total Mortality and Adverse Cardiovascular Ischemic Outcomes in Patients Undergoing Cardiopulmonary Bypass
- A Clinical Study Comparing Use of the Thoracic EXCLUDER Endoprosthesis to Open Surgical Repair in the Primary Treatment of Descending Thoracic Aortic Aneurysms
- Use of BioGlue Surgical Adhesive in Surgical Repair of Acute Thoracic Aortic Dissection
- Medtronic Heart Valves--U.S. Post Market Approval Study for MOSAIC Bioprosthesis Aortic Model 305/Mitral 310
- A Prospective, Randomized, Multi-Center of Mid-Term Vein Graft Patency Rates Using the St. Jude Medical Aortic Connector System vs. Standard Suturing Technique in Coronary Artery Bypass
Congratulations, Dr. Zehr!
Ross Zafonte, DO, chairman of the Department of Physical Medicine and Rehabilitation (PM&R) at the University of Pittsburgh School of Medicine and vice president of clinical rehabilitation services for the University of Pittsburgh Medical Center, is concerned with brain injuries to soldiers from explosions, such as those from roadside bombs used in Iraq. Even if there is no outward evidence of damage to a soldier’s head, invisible shock waves moving through the air can severely injure the brain, resulting in lifelong mental problems, speech impairments, memory loss, and sometimes death.
Because of improved body armor, soldiers today are surviving explosions that would yesterday cause serious injuries to their lungs, hearts, and other vital organs. The military reports, however, that among veterans from Iraq and Afghanistan treated at Walter Reed Army Medical Center in Washington, about 65 percent have traumatic brain injuries—an injury that other physical injuries might mask.
Testifying before Congress, Dr. Zafonte told Congress that nearly 2 million Americans suffer a form a traumatic brain injury every year, and about 50,000 die. He said, “This is probably the most under-sung disease…of our generation.”
Dr. Zafonte’s testimony was in support of the Veterans Traumatic Brain Injury Act. If passed, it would authorize more than $80 million to establish four Veterans Affairs centers across the nation for traumatic brain injury research and treatment. Veterans would be screened for it, and a registry for treatment would be established.
Dr. Zafonte is the principal investigator in a number of studies involving rehabilitation for traumatic brain injuries, the author of numerous publications about traumatic brain injuries and other rehabilitation topics, and he has also given more than 100 national and international presentations on these topics.
“I thank God every day,” says Amanda Goehring, a 27-year-old who runs her own business in nearby Evans City. The reason for her gratefulness? A mechanical heart pump she had in implanted in 2003. Back then she thought she had a bad case of the flu. But it was much worse. At age 23, she was in heart failure and fighting for her life.
Causes of heart failure include heart attack, high blood pressure, and attack by a virus. An invading virus is what left Amanda with an extremely weakened heart muscle and in cardiogenic shock. Her best option at the time was a transplant, but there was a chance she would not live long enough for a donor.
Fortunately, there was another option for Amanda: a mechanical heart pump, or ventricular assist device (VAD). First used in 1982, today’s VADs are more streamlined and permit the heart to rest and recover. In Amanda’s case, the heart went on to actually heal.
Amanda had a mechanical pump implanted at UPMC’s Presbyterian Hospital. It remained in place for about 2 months. An infection forced its removal sooner than originally planned, but her heart had recovered enough to take over without major problems.
UPMC emergency room practitioners are now changing their approach to treating acute heart failure patients. A team of doctors is being formed who will assess treatment options for those who come to the hospital in shock caused by a failing heart. Because of their success and popularity, VADs are a part of the therapy to give a heart the rest it needs to heal on its own.
Speaking about the benefits of VADs, Dr. Robert Kormos said, “You’re not asking the heart to work at the same time it’s trying to heal.” Dr. Kormos continues to express optimism about future developments in mechanical heart pumps, “I’m enthusiastic about the field opening up,” he said.
Taking the spark of an idea and moving it forward to a commercial reality is a slow moving process. Scientists hope the journey is a smooth one, but there’s always that occasional bump in the road. Therefore, each milestone reached is cause for celebration.
An innovative surgical adhesive from technology developed at the University of Pittsburgh by Drs. Eric Beckman and Michael Buckley has been awarded a US patent. The technology provides a platform for strong, resorbable adhesives for use inside the body. The technology is marketed by Cohera Medical, Inc. under license from the University of Pittsburgh.
Cohera's first product, TissuGlu™, a surgical adhesive, is currently in pre-clinical testing and is designed to provide optimal healing while minimizing fluid accumulation in tissues. Cohera has also won a second Phase 1 SBIR (Small Business Innovation Research) Award for the design and development of a bioresorbable bone adhesive for orthopedic use. The previous Phase I SBIR award was reported in the McGowan Institute’s July Newsletter. Dr. Beckman, Chief Scientific Officer and Co-Founder of Cohera Medical, will serve as the Principal Investigator on the bone adhesive study.
"The grant of Cohera's first patent reinforces the novelty of our core technology platform, and adds significant value to the company. The SBIR award further reinforces the breadth and potential for a variety of products that meet surgeons' needs across many specialties," said Patrick Daly, President and CEO of Cohera Medical.
A patent for preparing hydroxyapatite and using it in tissue engineering applications was recently awarded. Those who worked on the patent include McGowan scientists: Prashant Kumta, PhD, Charles Sfeir, DDS, PhD, Lee Weiss, PhD, and Phil Campbell, PhD. This technology provides a platform for bone and tooth engineering and repair applications and in gene delivery.
The Summary for Patent No. 7,247,288 reads: A novel method for making hydroxyapatite and the product of that method is provided. The method includes the step of reacting calcium ions with phosphate ions in the presence of hydroxyl ions at a ratio of calcium ions to phosphate ions is greater than 1.67, and typically greater than about 16.7 and even greater than 167. In one embodiment, the phosphate is trisodium phosphate and the calcium is calcium chloride.
Also provided is a hydroxyapatite complex in which the above-described hydroxyapatite is complexed with a biomaterial. In one embodiment, the biomaterial is plasmid DNA that contains a gene, such as a bone morphogenetic protein gene. Examples of suitable genes include rhBMP-2, Osx, Runx2, PDGF, NGF, VEGF, IGF, FGFs, EGF, TGF-.beta. and BMP-7.
The hydroxyapatite complex can be used to transform cells in vitro or in vivo. A method is therefore provided for transforming cells. The method includes the step of contacting a cell with the described hydroxyapatite complex. The hydroxyapatite may be associated with an appropriate tissue engineering matrix for use in regenerative medicine. A product including the described hydroxyapatite and a substrate, such as a bio-degradable porous natural and/or synthetic polymer, useful in tissue engineering and wound healing also is described.
Congratulations, Drs. Kumta, Sfeir, Weiss, and Campbell!
The Regenerative Medicine Podcasts continue to gain loyal listeners. There have been over 25,000 downloads to date. The most recent podcasts are:#39-Kim S. Jones, PhD, Assistant Professor, Department of Chemical Engineering, McMaster University. Dr. Jones’ research interests center on the interactions between tissue engineering and the host response. Her studies focus on 1) the host response to tissue-engineered constructs, and 2) the effect of host response on remodeling in tissue engineering. When a body receives an implant, it responds with scarring, inflammation, wound healing or regeneration. Therefore, tissue-engineered constructs will be remodeled once implanted. Her goal is to divert the remodeling response toward regeneration.
#38-Dr. Anshu Mathur of the MD Anderson Cancer Center at Houston ( a joint venture with the U. of TX at Austin and the U. of TX Health Science Center at Houston) discusses her lab’s research efforts which focus on the development of novel cell-responsive and regenerative-biomaterials engineered to locally control regeneration and therapeutic repair.Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Authors: |
Zheng B, Caro B, Crisan M, Sun B Li G, Logar A, Yap S, Pollett JB, Drowley L, Cassino T, Gharaibeh B, Deasy BM, Huard J, Peault B. |
Title: |
Prospective identification of myogenic endothelial cells in human skeletal muscle. |
Summary: |
Myoendothelial cells taken from the blood vessels are much more efficient at forming muscle than other sources of stem cells known as satellite and endothelial cells. A thousand myoendothelial cells transplanted into the injured skeletal muscle of immunodeficient mice produced, on average, 89 muscle fibers, compared with nine and five muscle fibers for endothelial and satellite cells, respectively. Myoendothelial cells also showed no propensity to form tumors, a concern with other stem cell therapies. |
Source: |
Nature Biotechnology. 2007 Sep;25(9): 1025-34. |
PIs: |
Jean Latimer |
| Co-PIs: | Stephen Grant and Michael Epperly |
Title: |
Biomarkers of invasiveness using isogenic and progressive human ductal carcinoma in situ cell lines |
Description: |
We have developed a novel tissue engineering system for Human Mammary Epithelial Cells (HMEC), both normal and malignant. This system allows for the long-term (>3 months) establishment of normal primary cultures that begin as 3-dimensional mammospheres. These mammospheres differentiate into complex branching ducts and lobules, i.e. reform the plumbing system of the breast in culture. The ability to form ductal structures from human breast tissue is absolutely unique to our laboratory. Tumor cells lack the ability to form these epithelial architectures. From these robust primary cultures we have generated 2 unprecedented DCIS cell lines from the same white patient¹s breast without the use of viruses or telomerase expression. We have now developed a set of biomarkers from microarray analysis that correlate well with invasiveness potential in these isogenic sets of cell lines. Validation of these biomarkers has been obtained using additional stage I and II cell lines we have also established, with known clinical recurrence patterns in the patients. In aim 2 we will validate the invasiveness of these cell lines by placing all DCIS and isogenically matched contralateral and non-tumor cell lines into transwell chambers and immunocompromised mice. Subcultures of the most motile cells will be analyzed in each case with microarray to validate the markers most associated with a motile and invasive phenotype. Concurrently, we will establish similar matched sets of DCIS cell lines from African American women. In women diagnosed with DCIS 1973-2000, 9.2% were White, 10.2% Black, 7.3% American Indian, 15.0% Asian/Pacific Islander, and 11.5% Other. Black women had a relative risk of mortality of 1.35 compared to white women, while Asian women had a reduced relative risk of 0.74, American Indian women had a RR of 0.95. The results we have obtained on the white and Asian women will be compared with those of the AA women in our study to assess whether DCIS, is associated with a higher risk of invasiveness in AA women. DCIS is one of the most commonly diagnosed forms of breast cancer (BC) because it is visible on mammograms. At the same time it is one of the least understood forms of BC with the likelihood of becoming invasive BC unknown. We have identified biomarkers associated with the early stages of breast oncogenesis using these unique progressive systems. We will further develop a population specific set of invasiveness markers for DCIS to assist in the tailoring of treatments for DCIS in African American women. |
Source: |
Komen for the Cure Agency |
Term: |
2 years, 5/1/07-4/31/09 |
Amount: |
$600,000 |
Newsletter Comments or Questions: McGowan@pitt.edu
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