ISCRM

Cardiovascular, Skeletal Muscle

Robert Boucek, Jr. (Chief of Pediatric Cardiology)
Development of cell therapies for pediatric cardiology.

Dan Bowen-Pope, PhD (Pathology)
The possibility that some vascular cells derive from extravascular progenitors is no longer controversial, but experimental limitations have prevented agreement as to the magnitude of the contribution, whether/when it is physiologically significant, and whether it can be manipulated for clinical benefit. We will trace, and specifically ablate, vascular endothelial cell and smooth muscle cell lineages using cell type-specific expression of reporter/effector fusion proteins that include EGFP and a domain that mediates apoptotic cell death when activated by injectable dimerizer. Using mice with transgenic bone marrow systems, we will:

  1. quantitate the contribution of bone marrow-derived progenitors to new vessel formation,
  2. determine whether vascular cells derived from extravascular vs local vascular sources differ in final phenotype, and
  3. use the dimerizer-activated apoptotic effector to evaluate the function of extravascular progenitors by selective ablation of this contribution during new vessel formation.

Jeff Chamberlain (Pathology)
Our Center is focused on developing a gene therapy-based treatment for the muscular dystrophies. Our investigators have published results showing the ability to halt muscular dystrophy and achieve a significant extension of lifespan in adult mice with dystrophy, the first group in the words to accomplish such a feat. Members of our Center have also recently received an NIH program project grant to develop stem cell based therapies for the muscular dystrophies, and have made pioneering studies of a new type of adult muscle stem cell.
Several unique features of the Seattle area have combined to enable the development of the world renowned excellence in muscular dystrophy research. As mentioned, we have an extremely large group of physicians and scientists working together on the disease. In addition, the Seattle area has one of the largest concentrations of scientists working on the development of gene therapy for many different diseases, and the expertise of those gene therapists has directly stimulated our own work on muscular dystrophy. Also, the UW has one of the few University operated Cell and Gene Therapy Laboratories, locate din our hospital to facilitate clinical trials of cell and gene therapies. Finally, the Seattle area is also well known for pioneering work in stem cell technologies, particularly in the hematopoietic stem cell fields, and the large number of labs working on stem cells has also greatly facilitated the newer work on muscle stem cells. Partly in recognition of the importance and depth of the cell and gene therapy work on muscular dystrophy in Seattle, Dr. Chamberlain, the director of the Seattle Muscular Dystrophy Research center has been named a member of the Food and Drug Administration's Cellular, Tissue and Gene Therapies Advisory Committee for the Center for Biologics Evaluation and Research, is a member of the Scientific Advisory board of the National Gene Vector labs.
Finally, another feature of the Seattle area that facilitated the push for gene therapy trials of muscular dystrophy is that the American Society for Gene therapy (ASGT) was founded by the UW’s Dr. George Stamatoyannopoulos, and at least 5 faculty members at the UW and FHCRC have served on the board of directors of the ASGT.

Martin K. (Casey) Childers, DO, PhD (Rehabilitation Medicine)
Gene therapy for myotubular myopathy, a congenital muscle disease, that causes severe and fatal weakness of the breathing muscles is a focus of the Childers lab. Our group is leading the development of this new gene therapy technology to translate findings in animals to treat human patients. The Childers lab also uses a technique to “reprogram” small samples of patient blood or urine into pluripotent stem cells that can be tested in a petri dish without harm to the patient. Using these powerful techniques our hope is to find and develop new therapy for inherited muscle diseases.

Michael T. Chin, MD, PhD (Medicine)
I am interested in several questions regarding regeneration of the heart. Specifically, I am interested in identifying and characterizing genes that promote the differentiation of stem cells into heart and vascular cells; identifying ways to promote the maturation of immature cardiac cells into mature and functional cardiac cells, and in identifying ways to convert existing fibroblasts into mature cardiac cells. Ultimately we hope to develop a personalized medicine approach where patient derived cells can be harvested and banked for future use in regenerating damaged hearts.

Cecilia Giachelli (Bioengineering)
My lab is interested in applying stem cell and regenerative medicine strategies to the areas of ectopic calcification, tissue engineering, biomaterials development and biocompatibility.

Stephen Hauschka (Biochemistry)
This lab studies developmental mechanisms responsible for directing mesodermal cells toward the skeletal and cardiac muscle cell lineages, and they work with the natural stem cells (satellite cells) of adult skeletal muscle that are responsible for muscle repair.

Brian Kennedy (Biochemistry)
We are currently studying the role of A-type nuclear lamins on adult muscle satellite cell function. We have determined that satellite cells lacking A-type lamins have differentiation defects. We plan to pursue the role of A-type lamins in stem cell maintenance in the future by determining the differentiation potential of embryonic stem cells induced to differentiate down different lineages.

Deok-Ho Kim (Bioengineering)
Through the use of multiscale fabrication and integration tools, Dr. Kim's research focuses on the development and applications of biomimetic cell culture models and functional tissue engineering constructs for high-throughput drug screening, stem cell-based therapies, disease diagnostics, and medical device development.

Michael Laflamme, MD, PhD (Pathology)
My laboratory is broadly interested in cardiac applications for human embryonic stem cells (hESCs) and, in particular, in the electrophysiologic properties and specialization of cardiomyocytes from this source. Having previously shown that hESC-derived cardiomyocytes can form implants of human myocardium in uninjured and experimentally infarcted rodent hearts, we are now focusing on determining whether these grafts show appropriate electrical integration with the host. We are also characterizing the baseline electrophysiologic properties of individual hESC-derived cardiomyocytes and plan to investigate how these properties might change with development either in vitro or in vivo. Finally, we have the longer-term goal of isolating specialized pacemaker and/or cardiac conduction system cells from hESCs, using guided differentiation or genetic selection with candidate promoters.

David L. Mack (Rehabilitation Medicine)
The Mack laboratory combines stem cell and gene therapies to develop new treatments for neuromuscular diseases. Induced pluripotent stem cell technology is used to generate patient-specific stem cells that can undergo directed-differentiation to multiple lineages in culture. Three-dimensional scaffolds are also being employed to further differentiate each cell type into their more mature form. This so called “disease-in-a-dish” approach will enable us to study disease mechanisms, and to create novel drug discovery platforms. Drugs identified in this way are likely to work in the patient since the patient’s own cells were used as the screening tool. Diseases being explored include Duchenne muscular dystrophy, X-linked myotubular myopathy and autistic syndrome disorder.

Dr. Mack is a classically trained geneticist with expertise in developmental and stem cell biology. During his postdoctoral fellowship at the National Cancer Institute, he studied how the stem cell microenvironment controls cell fate during mammary gland development. His recent contributions to the field of regenerative medicine center on the interplay between a cell’s genetic program and it microenvironment during lineage commitment.

William M. Mahoney, Jr., PhD (Pathology)
Dr. Mahoney is a researcher in the Center of Cardiovascular Biology and Regenerative Medicine at the UW South Lake Union campus. Research in the Mahoney laboratory is centered on understanding the basic mechanism controlling cell differentiation. Areas of focus include: (1) the characterization of specific molecular signatures defining different vascular beds; (2) determination of the mechanism by which Regulator of G-protein Signaling (RGS) proteins mediate smooth muscle cell physiology during development and in response to disease; and (3) the signaling events controlling vasculogenesis, and ultimately arteriogenesis, of stem-cell grafts implanted into injured myocardium.

Elina Minami, MD (Medicine/Cardiology)
My work is linked closely with the mission of the Murry lab. Initially, my focus has been in the role of circulating progenitor cells in transplant arteriopathy, but it has now shifted in the area of small and large animal cardiovascular physiology.

Charles Murry, MD, PhD (Co-director ISCRM, Pathology)
Developing cell-based therapies for cardiovascular disease, utilizing adult and human embryonic stem cells differentiated in vitro into cardiomyocytes, endothelial cells or their progenitors prior to delivery to diseased cardiac tissue.

Anna V. Naumova, PhD (Radiology)
I am interested in use of non-invasive imaging and magnetic resonance spectroscopy to study structural, functional and metabolic regeneration of the injured heart after transplantation of human stem cell derived cardiomyocytes. I am developing novel genetically-encoded markers to enable multimodality imaging of live cells (MRI, bioluminescence, fluorescence, and positron emission tomography). I have a deep interest in stem cell biology, molecular cloning, heart physiology and pathophysiology, cardiac MRI and image localized MR spectroscopy.

Roberto Nicosia (Pathology, VA)
Angiogenesis plays an important role in the progression of cancer but also contributes to the revascularization of ischemic organs and tissue regeneration. Vascular stem cells actively participate in the formation of new blood vessels during embryonal development and in adults. The molecular mechanisms by which these cells promote angiogenesis have not been fully characterized. Using in vitro and in vivo models pioneered in our laboratory we are studying cellular and molecular mechanisms by which blood vessels regulate angiogenesis. Our studies indicate that vascular stem cells actively participate in this process and play an important role in the formation of the vessel wall. Our long term goal is to identify key mechanisms that turn angiogenesis "on" and "off", and define the role of vascular stem cells in these processes.

Michael Portman (Pediatrics)
My laboratory studies modulation of cardiac metabolism in order to improve cell viability and recovery after injury. We are hoping to expand our research to include the paracrine influence of stem cells on metabolism of regenerating heart tissue.

Bensheng Qiu (Radiology)
Dr. Qiu is focusing on developing various molecular MRI techniques for stem cell-gene therapy, such as molecular MRI of neural stem cell-based gene therapy for brain tumors, MRI of vascular gene therapy and interventional MRI, and translating these new techniques to clinical applications.

Buddy Ratner (Bioengineering)
Stem cells proliferate and differentiate in response to micromechanical cues, surface biological signals, orientational directives and chemical gradients. To control stem cell proliferation and differentiation, the Ratner lab brings 30 years experience in surface control of biology, polymer scaffold fabrication and controlled release of bioactive agents to address the challenges of directing stem cell differentiation and subsequent tissue formation.

Michael Regnier, PhD (Bioengineering)
The Regnier lab works in a highly collaborative environment to develop both cell replacement and gene therapies approaches to treat diseased and failing hearts and skeletal muscle. Cell replacement strategies include development and testing of tissue engineered constructs. Gene therapies are target and improve myofilament contractile protein function.

Morayma Reyes, MD, PhD (Pathology)
The focus of Dr. Reyes' research is to study stem cells derived from skeletal muscles and heart as well as other major angiogenic populations important for tissue regeneration. The ultimate goal of her research is to apply this knowledge to develop cell therapeutics for treatment of muscle diseases such as muscular dystrophies and peripheral vascular diseases.

Michael Sobel
The Vascular Research Laboratories of the Department of Surgery at the VA Puget Sound HCS are led by Michael Sobel, Professor and Vice Chair, and Dr. Errol Wijelath, Research Asst. Professor. This group has been a leader in research on adult stem cells and endothelial progenitor cells, since Dr. Wijelath's seminal publication proving that prosthetic vascular surfaces can become endothelialized from the hematogenous deposition of circulating adult stem cells. Currently the group has an NIH award supporting their work on developing novel molecules to enhance angiogenesis within vascular prostheses, and to promote differentiation of adult stem cells to the endothelial line.

April Stempien-Otero, MD (Medicine/Cardiology)
We are interested in the role of bone marrow derived cells in cardiac repair and regeneration. Our specific research lies in how bone marrow derived cells direct the accumulation of excess collagen (fibrosis) in the heart and how that process can be reversed to allow optimal endogenous or exogenous cardiac regeneration. Using a human model we are testing the hypothesis that direct injection of these bone marrow derived cells can alter fibrosis and improve blood vessel formation in hearts with end stage ischemic heart disease.

Gale Tang, MD (Surgery)
The Tang lab focuses on peripheral vascular disease and new therapies for patients facing limb loss from arterial ischemia. I am interested in discovering cellular and molecular mechanisms of collateral artery development, or arteriogenesis. I hope to gain some understanding of the role of mesenchymal stem cells in this process, and how these cells can be modified to enhance collateral artery development to prevent limb loss.

Rong Tian (Anesthesiology & Pain Medicine, and Bioengineering)
My lab is interested in the role of mitochondria and cell metabolism in cell differentiation and in particular, in the maturation of cardiac myocytes.

Thomas N. Wight, PhD (Benaroya Research Institute)
This investigator leads a research program focused on the role that the extracellular matrix molecules, proteoglycans and hyaluronan, play in regulating vascular cell type and the regulation of extracellular matrix assembly. These pathways are fundamental to understanding the growth of new blood vessels in different tissues of the body, and have potential for direct tissue regeneration applications through the use of proteoglycan genes to bioengineer vascular tissue.

Zipora Yablanka-Reuveni (Biological Structure)
Skeletal muscle growth and regeneration depends mainly on myogenic stem cells that reside on the myofiber surface (i.e., satellite cells). Recent studies have suggested that uncharacterized stem cells residing in the vessel wall might be able to contribute myofiber nuclei as well. We investigate the function of both type of progenitors throughout the lifespan. Our research has the potential of contributing to the enhancement of the performance of resident (endogenous) myogenic stem cells in the aging muscle as well as for the development of cell-based therapies that can become useful to combat muscle lose following major muscle trauma and in myopathies.

Xiaoming Yang, MD, PhD (Radiology)
Dr. Xiaoming Yang's research team is focusing on fully applying the advances of modern imaging modalities to regenerative medicine, primarily developing new imaging techniques to monitor and guide stem cell-based therapies of life-threatening diseases, such as atherosclerotic cardiovascular disease and cancers.

Chun Yuan (Pathology)
Imaging, as already identified as a core of the institute, can play key roles in many different areas in stem cell research. One apparent area would be to monitor the therapeutic effects in tissue function as in the treatment of stroke, multiple sclerosis, spinal cord injuries, liver disease, and pancreatic islet cell transplantation. The most advanced area of research involves the use of stem cells to treat heart conditions, including the repair of myocardium after infarction. Most of the current works are in varies animal models but can be extended into human imaging. Stem cell tracking by invasive and non-invasive imaging is also being developed as part of the overall efforts in molecular imaging. This capability will be beneficial.

Ying Zheng, PhD (Bioengineering)
Dr. Zheng's research focuses on understanding and engineering the fundamental structure and functions in living tissue and organ systems from nanometer, micrometer to centimeter scale.

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