Program Faculty
Training Faculty Profile
The faculty members of the program investigate aspects of tissue bioengineering, cellular and molecular mechanisms of human disease and regenerative processes. Brief descriptions of the faculty research interests appear below:
Stephen Badylak (MIRM and Bioengineering) Tissue engineering, biologic scaffolds, and extracellular matrix biology
Our laboratory is focused upon the translation of tissue engineering principles to the clinical setting. We have successfully implemented the use of biologic scaffolds composed of naturally occurring mammalian extracellular matrix (ECM) into human clinical practice. Our present efforts include studies to better understand the signals that control the host response to implanted scaffold materials; especially biologic scaffolds. We have major efforts in progress in the areas of composition and ultrastructure of the ECM/cell signaling, and environmental cues that regulate host response to injury and tissue reconstruction. There is an equal balance between federally sponsored research efforts and industry sponsored research efforts in the laboratory. Our clinical translation efforts are focused upon esophageal replacement in patients with Barrett’s Esophagus, the repair and reconstruction of musculotendinous structures, and digit regeneration. The lab is interdisciplinary and staffed by a rich mixture of biologists, engineers, chemists, physicians, and scientists.
Ivet Bahar (MIRM & Molecular Genetics & Biochemistry) Computational Biology
Our interested is to gain an understanding of the molecular basis of biological function by characterizing of biomolecular systems. We use computational and mathematical models of different complexities for simulating dynamic processes at different levels. We focus on the conformational dynamics of proteins, including folding, domain movements, and/or local fluctuations, and their perturbation by ligand binding. We also use methods of reaction kinetics of modeling and analyzing the dynamics of cellular networks. These approaches are becoming increasingly more important with rapid advances in genome sequences and structures, and the accumulation of sequence, structure, and pathways data.
Eric J. Beckman (MIRM & Chemical Engineering) Polymer design for biomaterials
Our group examines the design of novel polymer systems for use in tissue engineering, where the design strategy creates molecular solutions to physiological constraints. For example, a degradable polyurethane was designed to promote the growth of osteoblasts for ultimate use in bone tissue engineering. Here, polymeric building blocks (lysine di-isocyanate, glucose, polyethylene glycol) were chosen so as to provide benign fragments upon degradation. By employing an isocyanate-terminal prepolymer, problems with free isocyanate are avoided and the polymer can be injected as a liquid which then cures upon contact with moisture. Further, bioactive compounds (ascorbic acid, dexamethasone), which are often used in culture media for osteoblasts, were covalently incorporated into the polymer which promoted superior cell growth.
Harry Blair (MIRM and Pathology) Tissue-Engineering and Cellular Therapy-Related Activity
We study skeletal remodeling using human and transgenic mouse models. The principal human models we use are
in situ differentiation of stem cells, either mesenchymal stem cells to produce osteoblasts or CD14 monocytes to produce osteoclasts. These models are used to create normal non-transformed tissues in vitro, and are directly related to the Bio-engineering and Cellular Therapy goals of the training grant
In vitro modification of cellular activity includes projects with TAT-labeling for protein uptake, plasmid transfection, and antisense gene suppression projects. These have been applied to calcineurin activity in osteoclasts (TAT-calcineurin Aa), suppression of estrogen response in osteoblasts by stable antisense plasmid transfection of ERα or β in human osteosarcoma cells, and suppression of NADPH oxidase in human osteoclasts by antisense oligomer suppression of multiple enzyme subunits.
Harvey Borovetz (MIRM and Bioengineering) Cardiopulmonary Organ Replacements
We are applying tissue-engineering technologies towards the development of cardiopulmonary organ replacements for adult and pediatric patients. Our current efforts are focused on the development of pediatric ventricular assist devices (PVAD) for infants and small children (3 kg - 35 kg; 0.5 liters per minute to 3.5 liters per minute flow rates) with congenital and/or acquired cardiac defects. Our PVAD concepts include the design of small diameter inflow/outflow cannulae that will not narrow and restrict flow for up to six months implantation. A second design goal is for a percutaneous lead that is anchored to the exit site and also provides adequate strain relief, thereby promoting complete healing with the surrounding tissue (thereby minimizing infection at the percutaneous exit site).
Robert Bowser, Ph.D. (MIRM and Pathology): Biomarkers of disease and regeneration in motor neuron disease
Transcriptional regulation and post-translational modifications to proteins are crucial components of cellular differentiation, homeostasis and cellular survival during injury and disease. Our group investigates a group of interacting transcriptional regulators that modulate neuronal differentiation and how these particular proteins also function to regulate neuronal survival or death in neurodegenerative diseases including Alzheimer disease and amyotrophic lateral sclerosis (ALS). Current research projects include the development of therapeutic strategies to protect motor neurons during ALS using
in vitro and
in vivo models. We also use mass spectroscopy based proteomics, metabolomics, and whole genome wide association screens to indentify biomarkers for ALS for diagnostic purposes and to define new therapeutic targets. Our laboratory participates in clinical trials for ALS and students will directly see how basic research can be translated to the clinic.
Charleen T. Chu, MD, PhD (MIRM and Pathology) mechanisms of oxidative neuronal injury and neurodegeneration
A long-term goal of my research is to understand mechanisms of oxidative neuronal injury and neurodegeneration, which can be therapeutically targeted to promote regeneration of functional circuits. We hypothesize that protective/reparative responses are activated during injury, but prove inefficient or even maladaptive in certain contexts. Since neurons retain the capacity for neuritic/synaptic plasticity throughout the lifetime, identifying cellular mechanisms that tip the balance to favor regenerative remodeling represents a promising approach towards effective therapies for neurodegenerative diseases. We have focused our work on understanding injury responses of dopaminergic neurons, whose degeneration contributes to motor symptoms experienced by patients with Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, environmental intoxications, and hereditary parkinsonian syndromes. Mitochondrial oxidative stress is implicated in each of these conditions, and our data indicates that both transcriptional and autophagic responses to injury are dysregulated by oxidative stress, contributing to neurite retraction.
Jörg Gerlach (MIRM and Bioengineering) 3D culture, cell perfusion, bioreactors
Jörg C. Gerlach, M.D., Ph.D. from Charité Medical School of Humboldt University in Berlin is a world-renown expert in biohybrid liver development and bioreactor design for stem cell culture technologies. Gerlach benefits from an appointment in the Departments of Surgery and Bioengineering as a core faculty member of MIRM through which he will have access to undergraduate and graduate research assistants and become involved in graduate level teaching in the Department of Bioengineering. Dr. Gerlach’s research focus is on building bioreactor systems that combine synthetic components with human cells to create support therapies that can help to boost the patient’s own healing process by allowing the affected organ to rest and recuperate. The underlying premise is that an organ system can be functionally relieved or “unloaded” to facilitate this natural healing.
Patricia Hebda (MIRM & Otolaryngology) Airway Bioengineering
There are numerous medical needs for repair or replacement of tissues of the upper aerodigestive tract. These include defects of the skin, mucosa, muscle and cartilaginous framework, either congenital or acquired. Our research group is focusing on the application of engineered cells and tissues for the treatment of these clinical problems. Subglottic stenosis (SGS), for example, is a potentially fatal narrowing of the lumen below the larynx resulting from a hypertrophic response to injury. Standard surgical methods currently used to correct SGS are fraught with complications of postoperative scarring and merely delay the onset of airway obstruction. Our research in this area is focused on developing strategies for surgical repair of SGS and other similar mucosal wounds to improve healing based on the phenotypic expression of ideal or scarless healing exhibited by fetal skin and airway. An established theme in our research group is the fibroblast phenotype as a determining component of the wound healing response and wound healing outcome. One of the approaches we use involves the interaction between the fibroblast and the extracellular matrix;
in vitro cell-matrix model systems have been developed explore
in vivo responses of cell migration and matrix remodeling.
Johnny Huard (MIRM & Orthopedics) Musculoskeletal tissue engineering
We focus on muscle-based gene therapy and tissue engineering for application to the musculoskeletal system, mainly as related to Duchenne Muscular Dystrophy and orthopaedic diseases and injuries. Our long term goals include the development of biological approaches toward improved muscle healing. We use gene therapy, tissue engineering, and stem cell research to induce muscle regeneration without fibrosis. Much of our work focuses on the characterization of muscle-derived stem cells which we have shown to improve muscle regeneration in dystrophin deficient MDX mice.
Eric Lagasse (MIRM and Pathology) Stem Cells
Our research focuses on the development of novel cell-based therapies for patients suffering from degenerative diseases using stem/progenitor cells. In addition, we have established a Cancer Stem Cell Center, a collaborative effort between the McGowan Institute and the University of Pittsburgh Cancer Institute. Our current research includes: Identification, isolation, and characterization of stem/progenitor cells for liver diseases; Development of reliable and convenient assays for stem cells; In vitro and in vivo expansion of stem cells; Development of cell-based therapies for liver diseases. Identification of cancer stem cells and development of anti-cancer therapies
Jean Latimer (MIRM and Obstetrics and Gynecology)
Dr. Latimer's laboratory has developed a multiple-lineage tissue engineering system for primary culture of Human Mammary Epithelial Cells (HMEC). There are three unique features of this system: 1. it has a success rate of 100% at establishing primary cultures from reduction mammoplasties; 2. it produces unusually long-lived cultures (3 months or longer), and 3. these cultures progressively undergo ductal, if not lobular, differentiation
in vitro, effectively reiterating
in vivo organogenesis. One of the key factors in the timeline for differentiation
in vitro is race with African American breast tissue differentiating 11 days earlier than white breast tissue in this system. Dr. Latimer has also used this methodology to culture breast tumors as well as non-diseased tissue with a success rate of 85%. In these studies her laboratory measured DNA Nucleotide excision repair (NER) capacity as an etiological factor in breast tumorigenesis. She has shown that early stage tumors show a significant loss of NER compared to non-diseased breast reduction mammoplasty cultures.
Luyuan Li (MIRM and Pathology) Targeting Tumor Neovasculature
We are interested in the molecular mechanisms of vascular homeostasis. We discovered an endothelial cell-specific gene named vascular endothelial growth inhibitor (VEGI; TNFSF15). Our findings indicate that VEGI modulates growth and apoptosis of endothelial cells. Systemic administration of recombinant VEGI in animal models leads to eradication of tumor endothelial cells and inhibition of tumor growth. In addition, VEGI may take part in the regulation of inflammation and cancer cell immunosurveillance. We are studying the mechanism of VEGI action and the potential of this unique cytokine as an anticancer therapeutic agent. Another project involves an endothelial cell receptor tyrosine kinase, Tie2, and its ligand, angiopoietin-1 (Ang1). The function of Ang1 is to modulate vascular branching, pericyte recruitment, and endothelial cell survival. We found that engineered high levels of Ang1 in tumor models led to stabilization of tumor neovasculature, which may have limited the otherwise continuous angiogenesis in the tumor and, consequently, given rise to inhibition of tumor growth. We are studying this new paradigm in the light of pericyte-endothelial cell interaction and tumor microenvironment.
Steven R. Little (MIRM, Chemical Engineering, Bioengineering, Immunology) Smart Biotechnology for Immunotherapeutics and Tissue Engineering
Our laboratory is interested in engineering solutions to solving problems related to the human immune system and tissue regeneration. More specifically we are interested in: 1) manipulation of the immune system through multi-functional synthetic delivery systems that take advantage of molecular interactions between immune cells. 2) methods of levying the wound healing process through rational drug delivery strategies and materials which are engineered to favorably interact with cells. Efforts towards cancer therapy are currently geared towards the rational development of single dose vaccines through controlled release technology and also using biomimetic strategies to create smart delivery vehicles that can shift immune responses to optimally attack cancer. We also have active research into new materials which facilitate differentiation of stem cells and enhance tissue regeneration. Furthermore, given the importance of nutrient and growth factor diffusion in tissue engineering strategies, we are interested in bettering the delivery of such materials in tissue engineering using synthetic constructs.
Youhua Liu ( MIRM and Pathology) Cellular and molecular pathogenesis of renal fibrosis
Studies in Dr. Liu's laboratory are focused on dissecting the cellular and molecular pathways leading to chronic renal fibrosis, and exploring novel strategies for therapeutic interventions. Using a series of experimental approaches, we are addressing several fundamental issues in renal fibrosis, such as what types of cells produce a large amount of matrix proteins under pathologic conditions and how they are regulated. Current studies in our laboratory include: 1) to decipher the mechanism controlling the regulation of tubular epithelial to mesenchymal transition (EMT) in renal fibrogenesis; 2) to unravel the interactions and cross-talks of the intracellular signal pathways activated by anti-fibrotic hepatocyte growth factor and pro-fibrotic transforming growth factor-beta in kidney cells; 3) to develop novel therapeutic strategies aimed at ameliorating renal fibrosis and kidney dysfunction.
Kacey G. Marra (MIRM, Surgery and Bioengineering) Tissue engineering using Adipose-derived Stem Cells
Our laboratory pursues cellular therapies using adult stem cells derived from human adipose tissue. The potential of adult stem cells derived from discarded fat, or adipose tissue, in regenerative medicine is immense and significant. As 65% of Americans are overweight, adipose tissue represents a plentiful, attractive, and reliable source for somatic cells. In our laboratory, we routinely isolate adipose-derived stem cells (ASCs), from human and animal fat. We characterize the ASCs using flow cytometry, and by differentiation into multiple phenotypes, including osteoblasts, adipocytes, and smooth muscle cells. Within our laboratory, we utilize ASCs for soft tissue, bone and nerve regeneration as well as cell expansion in a 3D bioreactor. Our experienced team of research fellows and graduate, undergraduate and medical students, is committed to the clinical translation of ASCs.
Wendy Mars (MIRM and Pathology) Role of Plasminogen Activators in Tissue Remodeling
Liver is an excellent
in vivo experimental model of tissue growth and remodeling as it represents a normal organ that can fully regenerate in response to partial hepatectomy (PHx). Plasminogen activators and the proteins they interact with play a central role in normal development and growth although the exact way in which this occurs is unclear. As
in vivo differences in the liver may be a secondary response to signals from other organs, the system will be recapitulated
in vitro via three dimensional cultures and a liver "bioreactor" in a collaborative project with Dr. Linda Griffith from MIT. It is the latter part of this project that has a direct role for a CATER trainee.
George Michalopoulos (Pathology and MIRM) Liver regeneration
Whole animal studies in our research group have focused on the role of hepatocyte growth factor (HGF) in liver regeneration. Using three-dimensional culture systems, we have shown that all elements of hepatic tissue (biliary cells, hepatocytes, endothelial and stellate cells) can be induced to form and become organized in stereotypic hepatic histology under the influence of corticosteroids, HGF and epidermal growth factor (EGF). HGF and EGF are required for the formation of the biliary epithelium whereas corticosteroids are required for the induction of the transcription factor HNF4 and the separation of the biliary from the hepatocyte lineage. Hepatocytes in this system can undergo phenotypic redirection to become biliary cells in this system. Recent studies have shown that this also occurs in the liver in vivo. The cultures are used to provide information on the signals and cytokines required for de novo engineering of hepatic tissue in culture.
Satdarshan Monga (Pathology, Medicine and MIRM) Liver growth and development
The major focus of our research is to understand the biology of liver stem cells in developing liver. We have successfully utilized a novel embryonic liver culture system to reproduce the cellular events occurring during normal liver development. This has provided us with a system that can be manipulated to study effort of several growth factors of major developmental events during liver formation such as proliferation, apoptosis, linage specification, differentiation and trans-differentiation. The ultimate aim is to isolate and characterize a liver stem cell and investigate therapeutic transplantation of embryonic liver cultures in various enrichment states following growth factor treatment. In addition, out laboratory has identified one of the key stem cell regulatory pathways, the Wnt/beta-catenin pathway, as an important regulator of liver growth and development. We have generated several mouse models that exhibit various phenotypes based on under or over expression of beta-catenin in the liver, demonstrating the vital role this pathway in liver physiology and pathology.
Partha Roy (MIRM and Bioengineering) Cell migration, Cancer Biology, Signal Transduction
Prfilin-1, a ubiquitously expressed actin-binding protein important for actin assembly, has been recently implicated as a tumor suppressor protein based on its reduced expression in several types of invasive cancers (breast, pancreatic) and ability to suppress tunorigenicity when overexpressed in breast cancer cells. Previous work by us has shown that overexpresssion of profiling-1 significantly inhibits the migration of breast cancer cells. Involving a combination of molecular biology, cell biology, biochemical and microscopic imaging techniques, ongoing studies in the lab focus on identifying the molecular mechanisms underlying the tumorsuppressive action of profiling-1 and determining how various molecular perturbations of prfilin-1 affect the migration, invasion and metastasis of breast cancer cells. A parallel project in the lab focuses on studying the role of profiling-1 in endothelial morphogenesis and angiogenesis. Other research interests in the lab are to 1) identify molecular regulations and novel interacting partners of profiling-1 and 2) study protein-protein interactions in migrating cells.
Alan Russell (MIRM and Bioengineering) The interface between materials and biotechnology
We work at the interface between materials and biotechnology. We have interests in how to use biotechnology to create novel biomaterials and also on how to incorporate biologic functionality into existing materials. We have, for example, dissected the mechanism by which enzymes can catalyze the synthesis of a unique class of polyesters that have pendant reactive groups. The polymers, synthesized a one-step rapid biocatalytic reaction, are ideally suited as base materials for the generation of tissue engineering scaffolds. In another class of projects we are focused on understanding how to incorporate enzymes, antibodies and signal peptides into coatings and monolithic polymers. For example, we are designing thin urethane films which contain antibodies and enzymes to generate coatings that attract specific cells and interact with those cells using the bio-functionality in the coating.
Michael Sacks (MIRM and Bioengineering) Tissue biomechanics
My overall research focus is characterization and modeling of the structure-function-biomechanics of native and engineered soft tissues, and linking these studies to the underlying cellular mechanobiology. In particular, my laboratory has focused on the mechanical behavior and function of the native aortic and mitral heart valves, including the development of the first constitutive (stress-strain) models for these tissues using a structural approach. To acquire the necessary critical experimental data, my laboratory has developed several novel methods to quantify tissue structure and multi-axial mechanical testing techniques. By integrating the resulting experimental data obtained from both techniques, we have developed structural constitutive (stress-strain) models that directly integrate information on tissue composition and structure. These models avoid ambiguities in materials characterization, offering insight into the function, structure, and mechanics of tissue components. Recent work includes multi-scale studies of cell/tissue/organ mechanical interactions in native and engineered heart valves. I am particularly interested in determining the local stress environment for heart valve interstitial cells. This work aims to utilize an integrated experimental / multi-scale finite element approach to determine how hemodynamic loading on the valve translates to altered stress states on the valve interstitial cell function and, in-turn, changes in local extra-cellular structure / composition and valve function.
William Saunders (MIRM) stem cells in tumor cell populations
To examine the role of stem cells in the genomic instability of tumor cell populations. There is evidence that stem cells may be the key cell population involved in tumorigenesis. How much do these cells contribute to genomic instability in tumor cell populations? Is there are relationship between stem cell numbers in tumor populations and instability? We will use immunological markers to identify stem cells within the tumor population. We have a variety of cancer lines, some tumorigenic and some not, and we have a variety of genetic instability markers including multipolar spindles, anaphase bridges, lagging chromosomes and multinucleation which vary in frequency in the different tumor lines. At the moment we are concentrating on the CD44 marker and its possible role in polyploidy. CD44 is present on the cell surface, and the localization and presence of various splicing variants is visible in our cell lines and has been shown to be linked to tumor potential. We are working on a model whereby CD44 may trigger cell fusion and support polyploidy a proven predisposing factor for tumor formation in mice. To test this we will mark cells with GFP-histone or DS-red and look for mixed populations of yellow cells. Then we will try and correlate fusion and the presence of CD44 splice variant markers and cellular distribution.
Sanjeev Shroff (MIRM, Bioengineering and Cardiovascular Institute)Cardiovascular mathematical models
As an example of our research goals, we are examining the relationships between global left ventricular mechano-energetic function and underlying cellular processes, with a special emphasis on contractile and regulatory proteins. We are also interested in defining the mechanical and chemical regulators of these contractile and regulatory proteins and their role in the transition to overt heart failure in the setting of chronic pressure and/or volume overload. Novel experimental and mathematical model-based date analysis techniques have been and continue to be developed for this purpose. Whole heart, isolated muscle, and single cell experiments are performed using various animal models, including transgenic mice. We are currently using this basic information regarding structure-function relationships to develop novel inotropic therapies that are based on altering cellular composition using genetic means. This information can also be used to optimize the fabrication protocol for engineered cardiac tissue such that it possesses the desired contractile and energetic properties.
Donna Beer Stolz (MIRM, Pathology and Cell Biology) Imaging of liver regeneration
Our research currently involves angiogenesis in liver using regeneration following 70% partial hepatectomy as a model system concentrating on the role of specific growth factors, their receptors and extracellular matrices in the growth and differention process. These studies have been extended to liver transplant models by evaluating repopulation of liver sinusoidal endothelial cells damaged during reperfusion injury following cold ischemic storage.
Stephen Strom (MIRM and Pathology) Cell therapy
Our group was the first in this country to prepare human hepatocyte transplantation to treat liver disease in patients and has now performed hepatocyte transplants in approximately 25 patients. Transplants have been performed to support liver function in patients with liver failure and to try to correct metabolic defects in liver function by cell (hepatocyte) transplantation. This is a true example of translational research and regenerative medicine which is ongoing in the Institute. Our laboratory was the first to be approved by the FDA for the isolation of hepatocytes for patient transplants and is also active in the identification of stem cells from placenta and the induction of differentiation of the cells into hepatocytes, neurons and insulin producing cells. The ultimate goal of this research is to provide an unlimited source of cells for patient transplants. The laboratory has expertise in human liver isolation and culture and will be an active collaborator with the artificial liver projects described above.
David A. Vorp (MIRM and Bioengineering) Biomechanical Differentiation of Progenitor Cells
The overall goal of our work is to develop tissue-engineered blood vessels (TEBV) and tissue-engineered urethral wraps (TEUW) fabricated from a mixture of progenitor cells and a supporting scaffold ( fibrinogen, collagen, or a synthetic material), and to determine the effect of applied biomechanical forces on progenitor cell differentiation and TEBV and TEUW development. We are investigating the effects of cyclic in-plane strain and hydrostatic pressure on the differentiation of progenitor cells to smooth muscle cells (SMC), endothelial cells (EC) and urothelial cells (UC). The goal here is to utilize biomechanical forces as a tool to create autologous, fully functional, disease free SMC, EC and UC for vascular and urethral tissue engineering applications. We are also evaluating in-situ (or in-construct) versus in-vitro (or in cell culture) differentiation of progenitor cells as the optimal means to populate the TEBV or TEUW with cells. The TEBVs and TEUWs will then be optimized vis-s-vis functional, histologic and biomechanical endpoints by determining the effects of relative concentrations of the constituents and by using various “hemodynamic preconditioning” regimens.
William R. Wagner (MIRM and Bioengineering) Biomaterials for Cardiovascular Tissue Engineering
Our work in the area of cardiovascular tissue engineering grew from the observation that much of the early work in this field relied upon scaffold material such as poly(lactic-co-glycolic acid), which does not mechanically mimic the properties of soft tissues such as those of blood vessels and the heart. We have focused on the molecular design of thermoplastic elastomers that would be amenable to control at both the synthetic and processing stages to achieve scaffolds optimized for a given application. Our work to date has focused on applying these materials to the cardiac wall, as a reconstructive material and as a post-infract patch, and as a small diameter blood vessel scaffold. We are also beginning to apply these materials as reconstructive fascia materials for traumatic injuries seen in the military arena.
Simon Watkins (MIRM and Pathology) Pathogenesis of dystrophin related diseases
We focus on defining the pathogenesis of dystrophin related diseases and identifying potential therapies. All skeletal muscle fibers are enveloped in a sarcolemma, composed of the muscle fiber basal lamina, plasma membrane and underlying cytoskeleton. It is a highly complex structure and is critical in ensuring appropriate muscle structure and function. A subset of interconnected molecules within this structure may be defined as the dystrophin cytoskeleton. Mutations in these molecules are responsible for diseases including Duchenne muscular dystrophy (dystrophin deficiency), congenital muscular dystrophy (merosin deficiency) and the sarcoglycanopathies. In each case the failure of a single component of the dystrophin cytoskeleton leads to a debilitating, commonly lethal myopathy. We are interested in learning about the process of development, assembly and integration of the dystrophin cytoskeleton and its potential role(s) in establishing and maintaining normal muscle function.
Alan Wells (MIRM and Pathology), Cell Motility in Regeneration and Disease
We aim to understand cell migration in terms of how motility processes are regulated, and how this regulation of migration plays a role in physiologic and pathologic situations. We are integrating the knowledge gained from our biochemical and biophysical mechanistic studies into our investigations concerning conditions of dysregulated (tumor invasion) and orchestrated (wound healing and organogenesis) cell motility. As part of understanding the motility response, we are investigating both how this particular integrated cell response is selected from among others and the metabolic consequences of motility. This integrative approach provides reinforcing insights and novel avenues for exploration into the basic signaling pathways as well as functioning of whole organism. Furthermore, this approach has enabled us to employ cellular and tissue engineering principles to design surfaces that specifically promote cell motility or proliferation. In this matter, we aim to generate novel reagents to alter cell motility to enhance healing or limit tumor progression. The latter aspect we are pursuing novel studies in tumor metastasis in a innovative liver bioreactor.
Savio L-Y. Woo (MIRM and Bioengineering) Biomechanics of the Knee: Understanding Injury, Healing, and Repair
Currently, our research group is demonstrating that the healing ligament or tendon has a disorganized collagen matrix and inferior mechanical properties to the normal tissue. Studies have shown that small intestine submucosa (SIS), when used as a soft tissue scaffold, has the potential to restore the histomorphological appearance, biomechanical content and mechanical properties of healing tissues. Specifically in the ligament, the SIS treated medical cruciate ligament showed a 33% increase in tangent modulus, and a 50% increase in tensile strength compared to the non-treated group, indicating a better tissue quality. In the case of tendon, SIS has medicated quick tissue regeneration in a patellar tendon defect. At this time, we are working on further improving the SIS by both cell therapy and mechanical conditioning. Studies are under way to determine the efficacy of seeding bone marrow derived stem cells on the SIS to impact the healing response. These stem cells can also be genetically modified to tailor their behavior to the ligament or tendon environment. We are also developing collaborations with William Wagner and Kam Leong bioscaffold experts, to develop electrospun SIS nanofiber scaffolds for ligament and tendon repair. We believe that these novel approaches will enhance understanding of the mechanisms of ligament and tendon healing, and thus, help to develop a better clinical management strategy with improved outcomes.
Chuanyue (Cary) Wu (MIRM and Pathology) Cell-extracellular matrix adhesion
We are elucidating the molecular mechanisms by which cells control extracellular matrix assembly, adhesion and signal transduction. We are currently focusing on integrin-linked kinase (ILK), a key component of cell-matrix contact sites, in these processes. We previously identified a ternary complex consisting of ILK, PINCH and CH-ILKBP. Molecular, biochemical, biophysical and cell biological approaches are being used to determine the basis underlying the assembly, functions and regulation of the ILK complex and its role in the pathogenesis of human diseases associated with abnormal cell adhesion and matrix assembly.
Xiao-Ming Yin (MIRM and Pathology) Mechanisms of cell survival in tissue injury, regeneration and abnormal growth
Our research focuses on mechanisms of cell survival in tissue injury, regeneration and abnormal growth (cancer). We used both in vivo and in vitro systems. A major in vivo system we have been using is the liver. We examine the mechanism of hepatocyte apoptosis and liver injury in the context of death receptor activation. We also follow the consequence of the injury induced by carcinogen and then the process of tissue regeneration and eventually carcinogenesis. In the in vitro system, we are using both primary hepatocytes and transformed cell lines. We examine the molecular events in both models regarding the molecules involved for cell death and protection. The goal is to eventually develop effective ways to intervene the process at different signaling steps.
Abdolreza (Reza) Zarnegar (MIRM and Pathology) Liver Regeneration
We are dissecting the molecular mechanisms involved in the regulation of hepatocyte growth, liver homeostasis and fibrosis with emphasis on the role of polypeptide growth factors such as HGF and its receptor tyrosine kinase Met. Emphasis is placed on the role of epithelial-mesenchymal interaction in the liver and its contribution to tissue function, with particular focus on the interaction of hepatocytes and hepatic stromal cells, called stellate cells which are the major players in liver fibrosis, and the regulation of gene expression and hepatic differentiation using tissue culture and transgenic mouse models. Thus, bioengineering students performing dissertation research in this laboratory will be trained in the area of cellular and molecular biology and the importance of cell-cell interaction in tissue function.
