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Wednesday, August 16
7:30 Breakfast Workshops (Sponsorships Available)
Stem Cells/Tissue Models
8:15 Chair’s Remarks
| Plenary Keynote Presentations |
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8:25 Spatial-Mechanical Regulation of Morphogenesis, Malignancy and Therapeutic Responsiveness
Valerie M. Weaver, Ph.D., Assistant Professor of Pathology & Lab Medicine, University of Pennsylvania
Using a quantitative molecular approach, animal models, 3D mammary epithelial cultures
(MECs) and mechanically-defined extracellular matrices (ECMs) we have been studying how physical force could modulate the normal and malignant tissue phenotype. We found that malignant transformation of the breast is associated with a sustained and progressive increase in ECM stiffness. ECM stiffness elicits these cellular effects by driving integrin aggregation to facilitate focal adhesion maturation through enhancement of
Rho-dependent cell contractility. A growth factor transformed mammary epithelium that exerts abnormally high
integrin-generated tension could be phenotypically-reverted if Rho-dependent force was normalized. Intriguingly, we recently found that matrix stiffness also alters the responsiveness of an epithelium to exogenous death cues including gamma radiation, chemotherapy and immune receptor activators. Thus, tissue homeostasis and apoptotic responsiveness appear to be functionally-linked to tensional-homeostasis through
integrin-growth factor receptor-GTPase crosstalk. The relevance of this paradigm to tissue morphogenesis, malignant transformation and tumor therapy will be discussed. |
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9:05 Functional Tissue Engineering and Disease Models
David Kaplan, Ph.D., Professor and Chair, Department of Biomedical Engineering, Science and Technology Center, Tufts University School of Engineering
Tissue engineering, through the in vitro cultivation of human stem cells, bioengineered 3D scaffolds and bioreactors, provides new options for the study of tissue structure and function. These human tissues provide a new venue to the study of disease in vitro under controlled conditions that can fill an important gap between cell-based assays and human clinical trials.
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9:50 The Convergence of Science and Commercial Considerations in Tissue Engineering
James W. Burns, Ph.D., Senior Vice President and Head of Drug and Biomaterial R&D,
Genzyme
Tissue engineering can be considered to be the use of therapy for influencing biology locally to repair tissue, regenerate organs, or restore health. We have used biomaterials, cells, genes, and drugs in combination and on their own, for tissue engineering applications in
orthopaedics, burn repair and cardiovascular medicine. My talk will focus on the technical development of our tissue engineering approaches and lessons learned on how science and commercial considerations converge in developing successful tissue engineering therapies.
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10:30
Coffee Break, Poster and Exhibit Viewin
11:30 A Good Ending Makes a Good Beginning - Telomere Function in Stem Cells
David Keefe, M.D., James M. Ingram Professor and Chair, OB/GYN, University of South Florida
Telomeres have long been known to mediate senescence in somatic cells. Virtually all stem cells express telomerase, the enzyme responsible for maintaining telomere length, but mammalian oocytes and early embryos do not. So how do reconstituted embryos reset telomere length? Recent work from our laboratory has shown that early embryos can reset telomere length during early embryonic development even in the absence of
telomerase.
12:00 Challenges of Primate Embryonic Stem Cell Research
Carol Brenner, Ph.D., Associate Professor, Department of Biology, University of New Orleans
Embryonic stem (ES) cell research is controversial to some because producing ES cells requires destroying embryos. However, some of the surplus human embryos available from in vitro fertilization (IVF) clinics may have a high rate of genetic errors and therefore would be unsuitable for ES cell research. An insurmountable problem is that there are no human ES cells derived from in vivo-produced embryos to provide normal comparative data. In contrast, some monkey ES cell lines have been produced using in vivo-generated, normal embryos obtained from fertile animals; these can represent a "gold standard" for primate ES cells. In this review, we argue a need for strong research programs using rhesus monkey ES cells, conducted in parallel with studies on human ES and adult stem cells, to derive the maximum information about the biology of normal stem cells and to produce technical protocols for their directed differentiation into safe and functional replacement cells, tissues, and organs. In contrast, ES cell research using only human cell lines is likely to be incomplete, which could hinder research progress, and delay or diminish the effective application of ES cell technology to the treatment of human
diseases.
12:30 Reconstructing and Deconstructing the Progression of Human Squamous Cell Carcinoma in 3D Tissue
Models
Jonathan Garlick, DDS, Ph.D., Professor, Division of Cancer Biology and Tissue Engineering, Tufts
University
1:00 Lunch on Your Own
Exploring Screening Tools
2:00 Chair’s Remarks
2:05 Applications of ES
Cell-Derived Neurons in a High-Throughput Screen to Identify
Potentiators of the AMPA Subtype of Glutamate Receptors
Marsha Roach, MS, Scientist, Pfizer Global Research and
Development
Schizophrenia is a chronic, highly debilitating mental
disorder afflicting over 3 million individuals in the US.
Current antipsychotic therapy effectively treats the symptoms,
but not the cognitive deficits. Since hypofunction of
glutamatergic neurotransmission has been implicated in the
pathophysiology underlying schizophrenia, the identification of
compounds that potentiate the AMPA subtype of glutamate
receptors may offer therapeutic benefit. We have developed a
novel high throughput screen using murine embryonic stem
cell-derived neuronal cell types to identify compounds that
potentiate AMPA receptors. This technology was utilized in a
functional high-throughput screen for novel allosteric
potentiators of the AMPA subtype of glutamate receptor. Initial
validation studies confirmed the expected range of potencies for
reference compounds. Key benefits of this technology include the
capability for a full file screen using a single batch of cells
and the ability to assay endogenously expressed neuronal
receptors in physiologically relevant cell types.
2:35 High-Content Drug
Screening with 3-D Bioengineered Muscle
Herman Vandenburgh, Ph.D., CSO, Myomics, Inc.
Muscle (cardiac, smooth and skeletal) is a complex tissue
with numerous, interdependent biochemical pathways which
regulate muscle contractility. We have developed a high-content
physiological screening method for quantifying muscle force
generation using 3-D bioengineered muscle in a 96 well format.
Using an in vitro physiological assay will help identify
muscle-active compounds and eliminate those exhibiting adverse
side effects prior to testing in vivo. This technology is
currently used to screen for drugs capable of attenuating
skeletal muscle wasting disorders using primary adult rodent and
human skeletal muscle stem cells.
3:05 3D Culture of Ovarian
Follicles: From Immature Eggs to Live Births
Lonnie Shea, Ph.D., Associate Professor, Chemical and
Biological Engineering, Northwestern University
In vitro fertilization techniques are not applicable to all
women with compromised fertility. We have designed
microenvironments for the culture of immature mouse follicles
that enables coordinated growth of germ and somatic cells
leading to follicle growth and maturation of the oocyte, which
can be fertilized and subsequently re-implanted to obtain births
of healthy pups. Successful maturation results from soluble
factors in the culture media, insoluble factors in the 3D
environment, and the mechanical properties of the environment.
This 3-D culture model can serve as the basis for
high-throughput screening to identify drugs that promote or
limit follicle maturation. Additionally, this technology may
enable egg banking as a means to preserve fertility for cancer
patients or other fertility disorders.
3:35 Refreshment Break, Last
Chance to View Poster and Exhibits
4:15 Human Organoids for
Immunogenicity and Immunotoxicity Testing
Christoph Giese, Ph.D., Department Head, Tissue
Engineering-Cell Assays, ProBioGen AG
Preclinical evaluation of biological drug candidates, e.g.
antibodies, vaccines and growth factors, demands novel
predictive cell-based assays. Species specificity of those tests
is crucial for valid efficacy and side effect data.
Three-dimensional tissue culture of the respective species, e.g.
human, seems to be mandatory. In contrast to chemical drugs, any
injection of biologics induces a light to severe immune
response. In cases of vaccines this particular response is the
most wanted. For therapeutical antibodies for example,
immunogenicity is a no go criteria. We will present concepts of
organoid culture, to address vaccine efficacy and immunogenicity
of biologics. Complex co-cultures of human dendritic cells and
lymphocytes were performed in miniaturized perfusion cell
culture devices. Cytokine patterns, histological analyses and
cell imaging were used to evaluate functionality and
responsiveness of these tissue cultures. First attempts were
made to multiplex, miniaturize and automatize the systems for
later high content. Process performance was evaluated for
robustness, consistency and standardization.
4:45 High-Throughput
Approaches to Drug Delivery and Tissue Engineering
Daniel G. Anderson, Ph.D, Research Associate, Chemical
Engineering, Massachusetts Institute of Technology
The combinatorial, automated high-throughput synthesis and
evaluation of small molecules has revolutionized modern drug
discovery. We have developed platforms that enable the rapid
synthesis and testing of large libraries of synthetic
biomaterials for delivery of genes, RNA, and drugs, and for
characterization of cell interactions. Using the methods, we
have identified degradable polymers with excellent in vivo
delivery properties, and identified materials that offer new
levels of control over stem cell behavior.
5:15 Panel Discussion
5:45 Close of Day
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