April 2007 | VOL. 6, NO. 4 | www.McGowan.pitt.edu

Bruno Peault, PhD and his colleagues have identified that adult human adipose tissue is an accessible source of cells with multilineage potential, including the capacity for skeletal muscle differentiation.  While the identity, anatomical location, and differential ability of various adipose-derived cells for muscle regeneration remain unclear the goal of the current studies has been to prospectively identify, within adipose tissue, a cell population with a robust ability to repair skeletal muscle, a prerequisite for the selective use of certain adipose-derived cells to optimize cell-based treatments of muscular disorders. 

Peault and his colleagues identified four distinct populations of stromal cells from adult abdominal subcutaneous fat and sorted these to homogeneity based on differential expression of CD34, CD45 and CD146.  The research revealed the existence of cells localized within the walls of adipose tissue microvessels, which are endowed with high muscle regenerative ability. 

Pericytes, identified on tissue sections and cell isolates by expression of CD146 and absence of CD34, generated by far the highest number of muscle fibers, when compared to the other cell populations, when transplanted into cardiotoxin-injured muscles of NOD-SCID mice.  The long-term culture of pericytes did not compromise their muscle regenerative capacity, suggesting the expandability of these cells ex vivo for clinical use. 

These results suggest that the adipose tissue-derived pericyte is an attractive candidate for the cell therapy of muscle diseases, and also indicates the likely vascular origin of the elusive fat-derived stem cells.   

Publication: Molecular Therapy (2007) 15 5, 867-877

Steven Little, PhD has been selected as a Clinical Research Scholar (CRSP) through the K12 mechanism of the National Institutes of Health. This 4 year program's primary intent is to provide training toward independent status at the interface of the fields of Chemical/Bioengineering and Immunology/Transplantation.  Dr. Angus Thomson (Director of Transplant Immunology) of the Starzl Transplantation Institute will serve as the primary mentor on the award. The focus of research will be to engineer biomimetic immunotherapeutic strategies through the use of biodegradable materials and the principles of drug delivery.

Cook MyoSite Opens New Headquarters

Cook MyoSite, the cell therapy division of Cook Medical, is opening a new 22,000 sq. ft. headquarters facility at the RIDC Park in O’Hara Township. This state of the art facility includes laboratories that meet FDA Good Manufacturing Practice (GMP) requirements for cellular manufacturing.

Building on the pioneering work of University of Pittsburgh researchers, and under a license agreement with the University, Cook MyoSite Inc., is developing technology involving the use of autologous muscle-derived cells for treating urinary incontinence and other diseases. These autologous cells - cells taken from the patient - may also have the ability to repair other damaged tissues.

Cook MyoSite co-founders, Michael Chancellor, MD, and Johnny Huard, PhD, partnered in 1997 to develop muscle stem cell based therapies. In 2001, with funding from Indiana-based Cook Medical, they founded Cook MyoSite. The company has since completed the first North American trial using muscle-derived cells to treat urinary incontinence and has started a multi-center trial in Canada.  The first U.S. trial is scheduled to start at University of Pittsburgh Medical Center in 2007. 

Cook Myosite

From Idea to Reality … One Step at a Time

Several years ago, McGowan faculty Eric Beckman, PhD, and Michael Buckley, MD invented a novel medical adhesive technology.  To move the technology from bench to bedside, Cohera Medical was formed and the invention rights were licensed by the University to Cohera.

This week the NIH announced the recipients of its Small Business Innovation Research (SBIR) Program Awards.  The SBIR program encourages small business to explore their technological potential and provides the incentive to profit from its commercialization. By including qualified small businesses in the nation's R&D arena, high-tech innovation is stimulated and the United States gains entrepreneurial spirit as it meets its specific research and development needs.

Cohera Medical won a Phase I SBIR Award for $180,000 that will help in the development of its lead product, TissuGlu™.  This product is an easy-to-use, strong, and resorbable polymer adhesive aimed at fulfilling the market demand for a strong, safe tissue adhesive that will improve the wound closure process by positioning tissues for optimal healing while minimizing fluid accumulation.  Studies in the lab have demonstrated that the bond created with TissuGlu™ is as strong after one hour as a normal wound is after a week of healing. Because the adhesive is created from sugars and amino acids, the components it breaks down into are designed to be benign and to lead to virtually no immune system response.  Cohera anticipates full FDA approval for TissuGlu™ as an internal surgical adhesive by 2009. 

Read more…
Press
Cohera Medical

In the April 9, 2007, issue of The Journal of Cell Biology, Johnny Huard, PhD and colleagues report that female adult muscle-derived stem cells have higher muscle regeneration efficiency.  “Regardless of the sex of the host, the implantation of female stem cells led to significantly better skeletal muscle regeneration,” said Dr. Huard.

These results were discovered while working with a population of stem cells isolated in his lab while searching for a cure for Duchene muscular dystrophy.  Both female and male adult muscle-derived stem cells were injected into dystrophic mice.  Measurements were then taken to determine the cells’ ability to regenerate dystrophin-expressing muscle fibers.  The female stem cell populations had a higher regenerative index than their male counterparts.  The  journal article shows that cell sex is a variable that considerably influences muscle-derived stem cells’ regenerative abilities.

Read the recent press

A collaborative project between the Federspiel and Russell Labs has resulted in a method of making artificial lungs more efficient, using an enzyme that helps to remove CO2 from the blood. The result, they hope, will be a smaller device that can be used in a wider range of patients.  The smaller units that Drs. Federspiel and Russell envisage could be used to treat a much wider range of conditions, such as temporary lung infection caused by emphysema or lung damage resulting from smoke inhalation. Currently, people with these conditions are put on a ventilator, but the pressure this exerts on the lungs can cause further damage by stretching the tissue. "The more you can get the invasiveness down, the more applications for the device," Dr. Federspiel says.

Paper:  “Towards improved artificial lungs through biocatalysis”’ Biomaterials, Volume 28, Issue 20, July 2007, Pages 3131-3139; Joel L. Kaar, Heung-Il Oh, Alan J. Russell and William J. Federspiel

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The goal of the Cellular Approaches to Tissue Engineering and Regeneration (CATER) training program is to provide a solid foundation upon which to build a productive independent career in cellular and tissue-based therapy for human disease and injury. This goal is accomplished via a highly coordinated and mentored interdisciplinary training program with a combination of required and elective courses, research activities, and specialized training opportunities. The program incorporates faculty from the University of Pittsburgh’s Bioengineering Department, the McGowan Institute for Regenerative Medicine, and the University of Pittsburgh School of Medicine’s Department of Pathology to provide a unique educational and research experience at the leading edge of science with respect to cellular/tissue regeneration and engineering. This combination of training, faculty research interests, and coursework provides a rich educational experience and more numerous training opportunities for students than could be obtained within the individual university departments.

Some comments from recent graduates of the CATER program include:

The CATER training was essential to my decision to pursue a career in the tissue engineering approach to cancer biology.  Through the exposure of classes, lectures, and workshops, I was able to develop ideas and bases for interdisciplinary projects that are at the interface of tissue engineering and cancer research.

I feel the strength of the CATER program was the faculty within the two outstanding departments that were primarily responsible for the training.  This environment provided a unique opportunity for high quality training of students in both biomedical engineering as well as the biology of pathological diseases.

I gained a lot from the CATER experience.  It was great to work with students and professors from the Pathology Department and to learn from them.  The presentations, seminars, networking, brainstorming, and retreats were very helpful.  The more presentations and critiques a person is involved with, the better.

CATER offers trainees a wonderful experience to network in an interdisciplinary setting and to think outside the limits of one’s own area of research.  CATER trainees also get to network with faculty whom they might not otherwise get to interact with.  CATER courses are overall excellent.

Students enter the CATER program typically at the start of the second year of graduate school.  At this point the student will have passed the first year core requirements from either the University’s School of Medicine Interdisciplinary Biomedical Graduate Training Program or the Bioengineering Program and will have selected a laboratory and mentor for their thesis project. 

If you are interested in additional details on the program—its requirements, faculty, and curriculum—they can be found at http://www.mirm.pitt.edu/events/cater/cater.htm.  The call for next year’s nominees is expected May 2007.

The Pittsburgh Tissue Engineering Initiative (PTEI) has been awarded a 5-year, $1.25 million grant from the National Institutes of Health to develop a unique educational program focused on engaging middle school students, their teachers, and the general public in the wonders of tissue engineering and its applications.  PTEI’s partners in the award include the Carnegie Science Center of Pittsburgh (CSC), ASSET (Achieving Student Success through Excellence in Teaching), and the University of Pittsburgh Learning Research and Development Center.

This project provides support for an inquiry-based, permanent, 1,200 square foot exhibit on Tissue Engineering/Regenerative Medicine at the Carnegie Science Center (CSC) in Pittsburgh, PA as well as in four to five other science centers across the U.S. The exhibit primarily targets middle-school (6th- 8th) grade students and their teachers and focuses on the theme, A Starfish Can Grow A New Arm, Why Can't I? The interactive exhibit aims to make visitors aware of the field and promise of tissue engineering as well as highlight the significant strides Pittsburgh-based researchers are making within the field in order that they may be exposed to cutting-edge research in their own backyard.

The exhibit will first introduce the concept of tissue engineering by exposing visitors to the innate ability of lower life forms to regenerate lost body parts (e.g., starfish arms, zebra fish hearts, salamander limbs and tails). Visitors will be shown basic scientific concepts related to evolution within various lower species and will then move on to mammals, primates and human, the highest levels of organisms, which because of evaluation have largely -- but, not entirely -- lost this ability. A major thrust of the exhibit will be responding to the "Why Can't I?" dilemma by demonstrating that through one of today's newest areas of biomedical science, tissue engineering, scientists and engineers are learning to tap into the hidden regenerative ability in humans. The underlying basics of the science and technology of tissue engineering will be provided along with an outlook for the future. Balanced with this will be a sensitive exploration of the ethical issues, myths, and misconceptions that currently surround the field. 

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Nearly 900 students from 100 schools in 11 western Pennsylvania counties participated in the 68th Pittsburgh Regional Science & Engineering Fair held Friday, March 30, 2007. The Pittsburgh Tissue Engineering Initiative (PTEI) and the McGowan Institute jointly sponsored a prize on tissue engineering and the winning project was "Responsiveness of Dermal Fibroblasts to Growth Factors" that was prepared by Shivani Mehta from North Allegheny High School.

Shivani, an 11th grade student, found normal wound healing to be a complex, highly regulated dynamic process requiring coordinated responses of epidermis, dermis, and signaling growth factors. Adult wounds heal with scar, but fetal skin wounds heal scarlessly.

Ms. Mehta’s aim was to study the cell migratory behavior of fetal fibroblast and adult fibroblast on a fibronectin-coated surface and to investigate the stimulatory effects of growth factors on these two cell populations. She found that fetal and adult fibroblasts migrate faster in response to growth factors, EGF and PDGF, whereas basal cell migration was inhibited by TGFb1 and TGFb3 in fetal fibroblast but not in adult fibroblasts.

Thank you to the staff and judges Timothy Maul, Julie Myers-Irvin, Julie Phillippi, and Priya Ramaswami; and congratulations, Shivani!

Annually, Pittsburgh magazine commissions Castle Connolly Medical Ltd.’s physician-led research team to select top doctors on the national and regional levels.  The process follows a rigorous screening process, evaluating a candidate’s medical education, training and hospital appointments, and by surveying area hospital leaders and physicians.  This year the following McGowan Institute clinical faculty were recognized in the May issue of the magazine.  Read more…

• Gastroenterology: David C. Whitcomb, MD, PhD 
• Neurological Surgery: Douglas S. Kondziolka, MD   
• Neurology: Steven T. DeKosky, MD 
• Ophthalmology: Joel S. Schuman, MD 
• Orthopaedic Surgery: Freddie H. Fu, MD 
• Otolaryngology: Clark A. Rosen, MD and Barry Hirsch, MD
• Pediatric Transplantation: George Mazariegos, MD
• Physical Medicine and Rehabilitation: Ross Zafonte, DO
• Plastic Surgery: Ernest Manders, MD 
• Psychiatry: David J. Kupfer, MD 
• Surgery: 

• Michael T. Lotze, MD, PhD 
• Howard D. J. Edington, MD 
• Ron Shapiro, MD 

• Thoracic Surgery: Robert L. Kormos, MD 
• Transplantation Surgery: Amadeo Marcos, MD
• Urology: Michael B. Chancellor, MD

The Regenerative Medicine Podcasts continue to be well received. The most recent podcasts are:

#30 - Ajit Yoganathan, Ph.D.
Podcast #30 features Ajit Yoganathan, Ph.D., Regents' Professor, Associate Chair for Research, and the Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering at Georgia Institute of Technology. 
Dr. Yoganathan and his colleagues are focusing on the development artificial heart valves and the use of novel instrumentation such as Doppler ultrasound and magnetic resonance imaging to non-invasively study blood flow patterns in the heart. 
Dr. Yoganathan established and leads the Cardiovascular Fluid Mechanics Laboratory at Georgia Institute of Technology. The objective of this laboratory is to integrate biological knowledge with engineering principles to understand the function and mechanics of various cardiovascular diseases and help the cardiac surgeons in planning, developing and implementing novel surgical repair techniques using state-of-the-art technology available today. The key thrust areas of the laboratory are in understanding the function and mechanics of native and prosthetic heart valves and in correcting pediatric and adult congenital heart defects.

#31 – Rory Cooper, Ph.D.
Dr. Rory Cooper visits Regenerative Medicine Today and shares highlights of his exciting studies on rehabilitation. Dr. Cooper’s research interests include:

• Assistive Technology Design and Instrumentation
• Standards and Quality Assurance
• International Rehabilitation
• Assistive Technology Policy and Access

In addition, he was one of the organizers of the Quality of Life Technology (QoLT) Center that draws many people from multiple departments, schools and programs at Carnegie Mellon University and the University of Pittsburgh.
In this podcast, he highlights some of the promising initiates emerging from his laboratories and from the Quality of Life Technology Center.

Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.

Authors:	Peault B, Rudnicki M, Torrente Y, Cossu G, Tremblay JP, Partridge T, Gussoni E, Kunkel LM, Huard J.
Title:	Stem and Progenitor Cells in Skeletal Muscle Development, Maintenance, and Therapy
Summary:	Satellite cells are dormant progenitors located at the periphery of skeletal myofibers that can be triggered to proliferate for both self-renewal and differentiation into myogenic cells. In addition to anatomic location, satellite cells are typified by markers such as M-cadherin, Pax7, Myf5, and neural cell adhesion molecule-1. The Pax3 and Pax7 transcription factors play essential roles in the early specification, migration, and myogenic differentiation of satellite cells. In addition to muscle-committed satellite cells, multi-lineage stem cells encountered in embryonic, as well as adult, tissues exhibit myogenic potential in experimental conditions. These multi-lineage stem cells include side-population cells, muscle-derived stem cells (MDSCs), and mesoangioblasts. Although the ontogenic derivation, identity, and localization of these non-conventional myogenic cells remain elusive, recent results suggest their ultimate origin in blood vessel walls. Indeed, purified pericytes and endothelium-related cells demonstrate high myogenic potential in culture and in vivo. Allogeneic myoblasts transplanted into Duchenne muscular dystrophy (DMD) patients have been, in early trials, largely inefficient owing to immune rejection, rapid death, and limited intramuscular migration-all obstacles that are now being alleviated, at least in part, by more efficient immunosuppression and escalated cell doses. As an alternative to myoblast transplantation, stem cells such as mesoangioblasts and CD133+ progenitors administered through blood circulation have recently shown great potential to regenerate dystrophic muscle.
Source:	Molecular Therapy (2007) 15 5, 867-877

 

PIs:	Michael Sacks, PhD
Co-PIs:	William Wagner, PhD
Title:	Biomechanical Optimization of Tissue Engineered Heart Valves
Description:	The focus of this competitive renewal grant is a comprehensive biomechanical evaluation of the in-vitro phase of engineered tissue heart valve development.
Source:	NIH/NHLBI: R01  HL68816-01
Term:	2/01/07– 12/31/11

Newsletter Comments or Questions: McGowan@pitt.edu