September 2008 | VOL. 7, NO. 9 | www.McGowan.pitt.edu
Significant Findings re Sources of Adult Stem Cells
Dr. Bruno Peault and colleagues (1) published in the September 11, 2008 edition of Cell Stem Cell a paper entitled “A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs”. Dr. Peault and colleagues have prospectively identified perivascular cells, principally pericytes, in multiple human organs including skeletal muscle, pancreas, adipose tissue, and placenta. The study showed that perivascular cells purified from skeletal muscle or nonmuscle tissues were myogenic in culture and in vivo. Irrespective of their tissue origin, long-term cultured perivascular cells retained myogenicity; exhibited at the clonal level osteogenic, chondrogenic, and adipogenic potentials; expressed MSC markers; and migrated in a culture model of chemotaxis. Expression of MSC markers was also detected at the surface of native, noncultured perivascular cells. The study concludes that blood vessel walls harbor a reserve of progenitor cells that may be integral to the origin of the elusive MSCs and other related adult stem cells.
In a preview of the Peault manuscript (2) Dr. Arnold Caplan, Case Western Reserve University, notes that this is a “landmark paper which presents a large body of work that defines, refines, confirms, establishes, and validates both the in situ and in vitro links between adult mesenchymal stem cells (MSCs) and perivascular cells, summarily refereed to as pericytes.”
Dr. Caplan also notes that “although my colleagues and I have been working with marrow MSCs for over 20 years…we and others have never performed a comprehensive and detailed comparison of the in situ and in vitro traits and pericytes. The team led by Bruno Peault provides a solid set of observations that clearly links the MSC and the pericyte”
(1)Authors include: Mihaela Crisan, Solomon Yap, Louis Casteilla, Chien-Wen Chen, Mirko Corselli, Tea Soon Park, Gabriella Andriolo, Bin Sun, Bo Zheng, Li Zhang, Cyrille Norotte, Pang-Ning Teng, Jeremy Traas, Rebecca Schugar, Bridget M. Deasy, Stephen Badylak, Hans-Jorg Buhring, Jean-Paul Giacobino, Lorenza Lazzari, Johnny Huard, and Bruno Peault
(2)“All MSCs Are Pericytes?”; September 11, 2008 edition of Cell Stem Cell
The Peault manuscript has been selected as the McGowan Institute “Publication of the Month”; see http://www.mcgowan.pitt.edu/news/publications/ for additional details.
The McGowan Institute for Regenerative Medicine is pleased to welcome leading transplantation surgeon and stem cell researcher, Ira J. Fox, MD. Dr. Fox has been recruited to direct the new Center for Innovative Pediatric Regenerative Therapies, a joint program of the University of Pittsburgh School of Medicine’s Department of Surgery, the McGowan Institute, and Children’s Hospital of Pittsburgh of UPMC. Dr. Fox is former senior associate dean for research at the University of Nebraska College of Medicine.
“I am delighted to join the University of Pittsburgh and the outstanding research team at Children’s Hospital of Pittsburgh and the McGowan Institute for Regenerative Medicine,” said Dr. Fox. “The tremendously collaborative atmosphere that I have already found in my short time here gives me great confidence in what we will be able to accomplish.”
Over the past decade, Dr. Fox has devoted his research to developing alternative ways to regenerate damaged liver cells. He was involved in a groundbreaking treatment of metabolic liver disease using an infusion of human liver cells, first reported in the New England Journal of Medicine in 1998. Dr. Fox has also focused his efforts on overcoming barriers to the use of liver cell transplantation in the treatment of hepatic diseases. Other areas of Dr. Fox’s expertise include gene therapy and stem cell research.
“Ira Fox is recognized as a research pioneer with exceptional leadership skills. In the lab, his achievements are innovative,” said Arthur S. Levine, MD, senior vice chancellor, Health Sciences, and dean, University of Pittsburgh School of Medicine. “His expertise will be a real asset not only to the University, but to the whole region.”
Others at the Institute were quick to add their voice in welcoming and admiring the work of Dr. Fox. From Dr. David Perlmutter, chairman of the Department of Pediatrics, and scientific director, Children’s Hospital of Pittsburgh: “The addition of Dr. Fox to the faculty is a real coup for Pittsburgh.”
From McGowan Institute director, Dr. Alan Russell: “Liver regeneration is one of the body’s own natural miracles, and if we can discover how to harness this regenerative power elsewhere in the body, it could transform the way medicine is practiced.”
From Dr. Timothy Billiar, professor and chair, Department of Surgery: “Research that Dr. Fox and his colleagues are conducting today could have a real impact on the field of transplantation.”
We all wish Dr. Fox well as he begins his new duties at the Center for Innovative Pediatric Regenerative Therapies, where the initial focus will be on finding treatments for diseases resulting from liver cell dysfunction, and we also would like to join in expressing our own words of welcome for Dr. Fox.
Multiple McGowan Institute faculty members contributed to the successful application that resulted in a partnership between North Carolina Agricultural and Technical State University (NCAT), the University of Pittsburgh, and the University of Cincinnati (UC). The partnership is the recipient of a 5-year, $18.5 million Engineering Research Center (ERC) grant from the National Science Foundation (NSF). The much sought after NSF ERC grant supports large-scale university and industry collaborations on pioneering technologies considered important to future generations.
The NSF Engineering Research Center for Revolutionizing Metallic Biomaterials will focus primarily on producing three technologies:
- Biodegradable and self-adapting devices and smart constructs for craniofacial and orthopedic reconstructive procedures;
- Similarly behaving cardiovascular devices such as stents; and
- Miniaturized sensing systems that monitor and control the safety and effectiveness of biodegradable metals inside the body (a technology that could lead to responsive biosensors that could help doctors determine when and where diseases occur in the body).
Contributing McGowan Institute faculty include:
- Harvey Borovetz, PhD, deputy director of Artificial Organs and Medical Devices, McGowan Institute; chair, Bioengineering Department
- Xinyan Tracy Cui, PhD, assistant professor, Department of Bioengineering
- Prashant Kumta, PhD, Edward R. Weidlein chair, Swanson School of Engineering; professor, Departments of Bioengineering, Chemical and Petroleum Engineering, and Mechanical Engineering and Materials Science
- Kacey Marra, PhD, assistant professor, department of Surgery; director, Plastic Surgery Laboratory; co-director, The Adipose Stem Cell Center, Division of Plastic Surgery
- Charles Sfeir, DDS, PhD, associate professor, Department of Oral Medicine and Pathology
- William Wagner, PhD, McGowan Institute deputy director; professor of Surgery, Bioengineering, and Chemical Engineering; director of Thrombosis Research for the Artificial Heart and Lung Program; deputy director, ERC
- Savio Woo, PhD, DSc, University Professor, Bioengineering Department; founder and director of the Musculoskeletal Research Center.
As part of this research effort, dozens of engineers and doctors from universities and industries around the world will collaborate on the project announced September 4, 2008, to develop implantable devices made from biodegradable metals. The devices will be designed to adapt to physical changes in a patient’s body and dissolve once they have healed. Naturally dissolving plates, screws, stents, and other devices will reduce the need for follow-up surgeries as well as the potential for complications from these major orthopedic, craniofacial, and cardiovascular procedures. The end result is a savings of millions of dollars worldwide in patient medical expenses, not to mention the added pain and inconvenience attributed to these follow-up surgeries.
Barry London, MD, PhD, McGowan Institute faculty member, professor of medicine and chief, Division of Cardiology, was named one of 16 National Institutes of Health Pioneer Award recipients at a symposium on the NIH’s Bethesda, Md., campus. Dr. London is the first academic medical researcher from the University of Pittsburgh to receive the distinction.
The award gives Dr. London, who also is director of the UPMC Cardiovascular Institute, $2.5 million in direct costs from the NIH to conduct novel experiments to better identify patients at high risk for sudden cardiac arrest, for which no reliable drugs currently exist.
Dr. London and colleagues will develop two revolutionary techniques to image electrical activity in the heart. In the first project, Dr. London will adapt the most common clinical imaging technique, which is two-dimensional echocardiography (ultrasound imaging of the heart), to detect electrical activity of the heart in real time. In the second project, Dr. London and colleagues will develop a modified adult stem cell implant to detect nervous system activity affecting the heart.
He will be collaborating with Flordeliza Villanueva, MD, also a McGowan Institute faculty member as well as associate professor of medicine and director of non-invasive cardiac imaging at the Center for Ultrasound Molecular Imaging and Therapeutics, UPMC Cardiovascular Institute.
Dr. Villanueva and her colleagues at the Center will develop a novel electrically sensitive microbubble contrast agent, which is a tiny, inert gaseous bubble injected into the bloodstream, that when applied to ultrasound imaging, will visualize electrical activity within the heart muscle. “Dr. London’s concept of using microbubbles to non-invasively see pathways of electrical conduction in the beating heart is an ingenious idea which I found exciting from the moment he first discussed it with me,” she said. This project truly embodies the spirit of the Pioneer Award to support high impact, innovative work. I congratulate Dr. London on his receipt of this prestigious grant, and look forward to participating in this work.” If successful, the research will then be applied to humans.
We at McGowan Institute would like to join in wishing Dr. London congratulations and continued success with this project.
Maj. Gen. (retired) Gale S. Pollock, former Deputy Surgeon General of the U.S. Army, has joined the UPMC Eye Center as executive director of the nation’s first Center for Ocular Regeneration and Vision Restoration (CORVR). The center is a joint effort involving the McGowan Institute for Regenerative Medicine and the University of Pittsburgh School of Medicine. Gen. Pollock will oversee the Center’s development as it begins to take form, integrating basic and clinical research endeavors with a strong patient focus.
As executive director of CORVR, Gen. Pollock plans to enforce a comprehensive approach when addressing the needs of the blind, blending the latest technology with successful research and clinical innovations. She will recruit a range of experts to pioneer comprehensive, patient-driven research and clinical therapies.
“Gen. Pollock brings to the Center for Ocular Regeneration and Vision Restoration the same passion, commitment and leadership skills that led her to become Deputy Surgeon General and Chief of Army Nursing. We are tremendously excited and fortunate to have her as executive director of CORVR,” said Joel S. Schuman, MD, McGowan Institute faculty member, professor and chairman of the Department of Ophthalmology at the Univesrity of Pittsburgh and director of the UPMC Eye Center.
Gen. Pollock has assembled a distinguished U.S. Army career with broad experience in health care administration. She has served as a nurse anesthetist, hospital commander, Chief of the Army Nurse Corps, Deputy Surgeon General and Acting Surgeon General.
McGowan Institute faculty member Dr. Newell Washburn, assistant professor of Chemistry and Biomedical Engineering at Carnegie Mellon University (CMU) along with fellow CMU researchers, report that they have developed hyaluronic hydrogels that can provide scaffolding for the growth of bone cells. Drs. Washburn, Krzysztof Matyjaszewski, and Jeffrey Hollinger report their hydrogels have already shown promising results in encouraging the growth of preosteoblast cells--cells that aid the growth and development of bone.
Currently, physicians are able to treat patients with damaged bone tissue, like those who have bone fractures that fail to heal, using demineralized bone matrix, a biological material obtained from cadavers. Demineralized bone matrix is rich in growth factor proteins which signal bone cells in the area to multiply and form complex bone tissue, while other proteins in the matrix regulate the activity of the growth factors. Demineralized bone matrix is in limited supply, and because it comes from a human donor, there is a risk of transmitting viruses to the recipient.
“Tissue engineering is an exciting field. We’re creating solutions to problems that can significantly impact people’s quality of life. These gels have great promise in not only regenerating bone, but serving as a gene therapy delivery system,” said Dr. Washburn.
As reported by the Thaindian News, the researchers revealed they created a flexible hydrogel using biologically active and degradable hyaluronic acid. In lab experiments, the hydrogels promoted cell proliferation, differentiation, and mineralization of pre-osteoblast cells. Further research by the group created a hybrid hydrogel that incorporated a nanogel structure. The researchers revealed that the new hydrogel promotes the differentiation of cells, much like the hyaluronic acid gel, while also releasing nanogels in a controlled and targeted manner. They hope that this structure can be used to partner tissue engineering with gene therapy.
Read more…Carnegie Mellon University Press Release
McGowan Institute for Regenerative Medicine faculty member Michael Lotze, MD, director of Strategic Partnerships for the University of Pittsburgh Cancer Institute, co-directed a recent conference, the Third International Damage Associated Molecular Pattern Molecules (DAMPs) and Alarmins Symposium at the Hillman Cancer Center. The event marked the first time in the United States that more than 200 scientists from around the world gathered to explore research challenging conventional theories about immunology, inflammation, and their link to acute and chronic diseases
DAMPs and alarmins are the molecules in the body that promote healing after events such as heart attacks, strokes, and car accidents. According to Dr. Lotze, they promote an inflammatory response that comes from inside cells. In the past, it was believed that inflammation arose from forces outside the body, such as pathogens, while the DAMPs theory of inflammation suggests that it arises internally from the body's very cells.
“At this point, it is well-understood that continuous inflammation is also linked to chronic diseases such as diabetes, rheumatoid arthritis, and most cancers, particularly those occurring in adults,” said Dr. Lotze. “In the past, the prevailing scientific notion was that pathogen-associated molecular patterns, or PAMPs, cause inflammation by activating the immune system when pathogens such as viruses, parasites, fungi, and bacteria invade the body. This type of immune response occurs in the setting of infection. At this symposium, scientists present[ed] research linking the DAMPs inflammatory response to chronic diseases, including arthritis, obesity, atherosclerosis, and cancer.”
Dr. Lotze also holds a professorship of Surgery and Bioengineering, is vice-chair of research within the Department of Surgery, and is assistant vice chancellor of the six schools of the Health Sciences.
Read more…Pittsburgh Post-Gazette
Savio L-Y. Woo, PhD, DSc (Hon), University Professor of Bioengineering and the Director of Pitt’s Musculoskeletal Research Center (MSRC), received an Honorary Professorship from Beijing University of Aeronautics and Astronautics (BUAA) on August 14, 2008, while he and Mrs. Woo were attending the Olympic Games in Beijing as guests of International Olympic Committee (IOC) President Jacques Rogge. BUAA’s President Li, a member of the Chinese National Academy of Engineering, conducted the ceremony, and Dean Fan of the School of Biological Science and Medical Engineering introduced Dr. Woo.
The honor was bestowed upon Dr. Woo for his many contributions to Biomedical Engineering as well as his dedication to education. Dr. Woo will also serve as Chair of the International Advisory Committee of the School of Biological Science and Medical Engineering at BUAA.
In 1998, Dr. Woo was the winner of the IOC Olympic Prize for Sports Medicine and was awarded the first Olympic Gold Medal in Nagano, Japan. Dr. Woo is a McGowan Institute faculty member and serves on the Institute Executive Committee.
Photo caption: Dr. Woo with Mrs. Woo on his right. University President Li and Dean Yubo Fan are on Dr. Woo’s left along with other distinguished guests.
G. Bard Ermentrout, PhD, professor of Mathematics and adjunct professor of Neurobiology at the University of Pittsburgh, is a member of a team of project and core leaders which received a $10 million grant from the National Institute of Mental Health to support the new Conte Center for the Neuroscience of Mental Disorders (CCNMD). The CCNMD will focus on developing new treatments for schizophrenia, a disease that affects over 2 million adults in the United States alone. The grant will enable Pitt researchers to gain a better understanding of the disease process and to identify pathophysiology-based molecular targets for novel therapeutic interventions for this devastating mental illness.
The center’s research is based on the widely-replicated observation that expression of a gene that synthesizes the neurotransmitter GABA is reduced in the brains of individuals with schizophrenia. GABA, or gamma-aminobutyric acid, is an important neurotransmitter essential for core cognitive processes such as working memory. CCNMD investigators are working to understand how reduced GABA could lead to impairments in brain function that are typical of schizophrenia.
The CCNMD will provide a multidisciplinary approach to understanding the neurobiology of schizophrenia and includes specialists in molecular neurobiology, systems and computational neuroscience, brain imaging, and clinical psychiatry.
McGowan Institute faculty member Dr. Sanjeev Schroff, professor and Gerald E. McGinnis Chair in the Department of Bioengineering, is part of a group of researchers from the University of Pittsburgh, Magee-Womens Research Institute, and the University of California, San Francisco, who recently received a $6.4 million, 5-year grant from the NIH to study what role obesity may play in preeclampsia, a common complication of pregnancy that threatens the life of both mother and baby.
The grant is a renewal of funds originally awarded 14 years ago to support studies into the basic mechanisms of preeclampsia, but the focus on obesity is a new direction. The Pittsburgh group will study the interactions of proteins, lipids and other cellular components in an effort to discover important relationships between body weight and preeclampsia. Preeclampsia is most often characterized by high blood pressure and the presence of protein in the urine.
Nine other Pitt faculty members join Dr. Shroff in comprising this research group.
The NIH has granted Dr. Paul Monga a competing renewal of funding for his project on the role of Wnt/b-catenin signaling in liver development. Budgeted at $2.6 million, the research aims to understand the critical signaling pathways that dictate the processes of liver growth, regeneration, and development in order to identify the molecular basis of liver disease. Dr. Monga is a McGowan Institute faculty member as well as an associate professor of Pathology.
Dr. Monga’s research seeks to comprehensively examine Wnt signaling in liver biology to eventually improve the prognosis for patients with liver disease. His laboratory is focused on understanding the molecular mechanisms of liver growth and development in health and disease, especially trying to address the molecular basis of liver development, growth, regeneration, and cancer. Several signaling pathways have been identified to direct such events including the Wnt/ -catenin, HGF/Met, PDGFR and others.
Dr. Joel Schuman, McGowan Institute faculty member and chair of the Department of Ophthalmology, recently accepted on behalf of the department, a $110,000 grant from Research to Prevent Blindness (RPB), the leading voluntary health organization supporting eye research directed at the prevention, treatment or eradication of all diseases that threaten vision. The grant will be distributed throughout the department.
RPB provides major eye research funding to more than 50 leading scientific institutions in the U.S. and supports the work of hundreds of talented vision scientists engaged in a diverse range of disease-oriented research.
Dr. Schuman is currently leading the organization of the new Center for Ocular Regeneration and Vision Restoration, a partnership between the Department of Ophthalmology of the UPMC Health System and the McGowan Institute. At the University of Pittsburgh, Dr. Schuman is Eye and Ear Foundation Professor and also serves as director of the UPMC Eye Center.
The Regenerative Medicine Podcasts continue to gain listeners and explore pertinent topics. Remember to tune in and keep abreast of new interviews. The most recent podcasts are:
#55 – Newell Washburn, PhD – Dr. Washburn, a professor of Chemical and Biomedical Engineering at Carnegie Mellon University, discusses his work on wound healing and bone tissue engineering though the use of biomaterials that can be used to form novel polymeric scaffolds for regenerative therapy.#56 – Steven Little, PhD – Dr. Little, Assistant Professor and Bicentennial Alumni Faculty Fellow, Departments of Chemical Engineering, Bioengineering, Immunology, and Medicine at the University of Pittsburgh, introduces us to his pioneering studies in targeted drug delivery.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Mihaela Crisan, Solomon Yap, Louis Casteilla, Chien-Wen Chen, Mirko
A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs
Mesenchymal stem cells (MSC), the archetypal multipotent progenitor cells derived in cultures of developed organs, are of unknown identity and native distribution. We have prospectively identified perivascular cells, principally pericytes, in multiple human organs including skeletal muscle, pancreas, adipose tissue and placenta, on CD146, NG2 and PDGF-Rβ expression and absence of hematopoietic, endothelial and myogenic cell markers. Perivascular cells purified from skeletal muscle or nonmuscle tissues were myogenic in culture and in vivo. Irrespective of their tissue origin, long-term cultured perivascular cells retained myogenicity, exhibited, at the clonal level, osteogenic, chondrogenic and adipogenic potentials, expressed mesenchymal stem cell markers and migrated in a culture model of chemotaxis. Expression of MSC markers was also detected at the surface of native, non-cultured perivascular cells. Thus, blood vessel walls harbor a reserve of progenitor cells that may be integral to the origin of the elusive MSC and other related adult stem cells.
Cell Stem Cell. 2008 Sep 11;3(3):301-13.
Yoram Vodovotz, PhD
Gregory M. Constantine, PhD (Pitt—Mathematics); Steve Chang (CEO of Immunetrics); Drs. Gary Nieman and Kris Maier (SUNY-Syracuse)
Mathematical Modeling of Inflammation in ARDS
Trauma and systemic infection elicit an acute inflammatory response. Inflammation involves complex interactions among leukocytes, their products (cytokines, free radicals, and proteases), and the tissue damage/dysfunction that ensues. This multiple organ dysfunction often manifests as septic shock and severe lung dysfunction, referred to collectively as the acute respiratory distress syndrome (ARDS), and contributes to the 215,000 annual deaths in the U.S. from sepsis. The complexity of this process has stymied the progress towards immunomodulatory ARDS therapeutics. We have developed a mathematical model of these elements in order to unravel this complex interplay in various settings of acute inflammation, and have calibrated distinct variants of this model with data from mice, rats, swine, and humans (University of Pittsburgh Inflammatory Analyte/Modeling Component). Our modeling platform has been used to gain both basic and translational insights, the latter including simulated (in silico) clinical trials. In conjunction with these efforts, we developed a sepsis + gut ischemia/reperfusion (Sepsis+I/R) porcine model that mimics the pathogenesis of human septic shock and ARDS (Upstate Medical University ARDS Animal Model Component). We hypothesize that mathematical analysis of the complex biochemical and physiologic data generated in our Sepsis+I/R model will enable us to isolate key therapeutic targets and to test novel therapeutics; one such agent is the modified tetracycline COL-3. Our Specific Aims are: 1) to develop a robust mathematical model describing Sepsis+I/R-induced shock and ARDS in swine, its pathologic consequences, and possible therapies, 2) to utilize COL-3 as a tool to further calibrate the mathematical model and 3) to demonstrate that NE, MMP-2 and MMP-9 are critical components in Sepsis+I/R-induced septic shock and ARDS pathogenesis. Our calibrated mathematical model will be used to conduct in silico clinical trials and establish a platform for the rational development of novel ARDS therapeutics. The in silico trials will be validated in animal experiments. The proposed translational studies will develop a robust mathematical model capable of describing the complex pathogenesis of sepsis-induced ARDS and identify target molecules whose modulation would significantly improve clinical outcome.
NIH (National Heart, Lung and Blood Institute)
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