Presenter:  Steve Strom
Date:  Friday, January 18, 2008
Time:  1:30 pm – 2:30 pm
Location:  1101 Scaife Conference Center
Topic:  Stem Cells from Human Placenta

Presenter:  Dan Debra
Time:  12:30 pm – 1:30 pm
Location:  BST S218
Topic:  Relaxin Regulates Systemic Hemodynamics and Arterial and Vascular Wall Mechanical Properties
Description: Relaxin is a peptide hormone that emanates from the corpus luteum of the ovary and circulates during pregnancy.  Our previous work has shown that the hormone mediates the transition of the systemic circulation from the virgin to the pregnant state in the gravid rat model.  However, our recent work suggests that relaxin’s effects on the systemic circulation extend beyond pregnancy.  Specifically, we have shown that relaxin regulates systemic hemodynamics as well as vascular structure and mechanical properties in nonpregnant female and male rodents.  In addition, relaxin receptors have been detected at various vascular sites in male and female species and relaxin knockout mice have a phenotype that is opposite to that observed during pregnancy and relaxin administration.  In this seminar I will be discussing the effects of relaxin (both endogenously derived and exogenously administered) on systemic hemodynamics and vascular remodeling as well as the therapeutic potential for relaxin in modifying arterial stiffness and cardiac afterload.

Presenter: Jörg C. Gerlach
Time:  12:30 pm – 1:30 pm
Location:   BST S218
Topic:  3D perfusion bioreactor technologies for stem cell maintenance, differentiation and expansion in regenerative medicine
Description:  Tissue density bioreactors enable a spontaneous re-assembly of primary cells inoculated into a bioreactor and their establishment of a scaffold or biomatrix. A homogeneous mix of adult liver cells, e.g. from organ collagenase digestion containing parenchymal hepatocytes, non-parenchymal cells (such as sinusoidal endothelial cells, stellate cells, and liver progenitor cells) can restructure after injection into specific bioreactors to form well-defined liver structures, such as neo-sinusoidal structures and neo-spaces of Dissé, reminiscent of the native liver. Moreover, adult liver progenitors restructure anatomical structures resembling the Canal of Hering, the putative liver stem cell niche.

The current challenge that prevents stem cells from use in regenerative medicine applications is directing the full differentiation of their progeny in vitro. In order to further develop new therapies, adult and embryonic stem cell research focuses on maintenance, proliferation and differentiation, and tissue formation in vitro. Numerous groups already work on derivation and characterization of specific stem cell lineages, but the underlying mechanisms are only partly understood.

Several fundamental questions remain to be answered, e.g.:

• Can we control proliferation/differentiation of selected stem cells in vitro?
• Can we maintain the genotype/phenotype stability of selected stem cells in vitro?
• Can specific micro-environmental conditions be used to control in vitro maintenance of selected stem cells?
• Can, after inoculation of selected isolated stem cells, tissue restructuring be achieved by the cells themselves?
• Can tissue formation by selected stem cells be induced and controlled in vitro?
• Can we establish in vitro a tissue-density of a larger number of selected stem cells without central necrosis?
• Can a reproducible proliferation/differentiation and utilization of selected stem cells be achieved in vitro?
• Can specific macro-environmental conditions, such as 3D high-density co-culture with integrated oxygenation and decentralized mass exchange, be used to control in vitro maintenance of human embryonic stem cells in a larger cell mass?
• Can a phenotypic stabilization of selected stem cells and the maintenance of a liver progenitor cell pool be achieved by 3D high-density co-culture with integrated oxygenation and decentralized mass exchange?
• Does the integration of a more physiological tissue macro-environment, e.g. by hollow fiber membranes into a growing cell mass result in a genotypic/phenotypic stabilization of proliferating stem cells?
• Can we maintain the stability of human embryonic stem cells in vitro, while they are proliferating as a larger mass and differentiating towards hepatic cells?

For several topics, experimental animal source or biopsied human tissue, as well as conventional Petri- dish in vitro culture methods seem to provide appropriate tools for investigation. However, investigations focusing on the impact of exogenous factors could benefit from the use of purpose-built bioreactors that enable 3D high-density perfusion co-culture. There is a considerable need for such in vitro stem cell systems, since the stem cell-derived tissues must be capable of stable and long-term integration; into a bioreactor or, after transplantation, into existing physiological tissues, at least until they are replaced by the body’s own tissue repair process, or permanently if self-repair is not possible. At least some of such studies require reproducible and controllable in vitro conditions.

Presenter:  Lauren Kokai
Time:  12:30 pm – 1:30 pm
Location:  BST S218
Topic:  To Be Announced

Presenter:  Christi L. Kolarcik
Time:  12:30 pm - 1:30 pm
Location:  BST S218
Topic:  Characterization of retinoid signaling proteins in amyotrophic lateral sclerosis
Description:  Amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disorder and the most common form of motor neuron disease, is characterized by the progressive degeneration and death of motor neurons within the brain, brain stem and spinal cord.  Currently, established and objective molecular markers that allow for the diagnosis and monitoring of ALS are lacking and improved therapeutic interventions needed.  Our laboratory previously identified transthyretin (TTR) as a potential protein biomarker of ALS using mass spectrometry-based proteomics to profile cerebrospinal fluid of ALS and control subjects.  TTR functions within the retinoid signaling pathway important for modulating gene expression and protein aggregation.  This talk will discuss our characterization of retinoid signaling proteins in ALS.  We hope to provide much-needed insight into the molecular mechanisms underlying this condition and to identify novel targets for future therapeutic investigations for the treatment of ALS.

Presenter:  Lance Davidson
Time:  12:30 pm – 1:30 pm
Location:  BST S218
Topic:  Reverse-Engineering Morphogenesis
Description: The control of morphogenesis is one of the most complex problems of modern biology and tissue engineering. Morphogenesis requires the coordination of tissue mechanics with cellular processes such as motility and shape changes. Advances have been made to understand the molecular regulation of cell motility, patterning, and signal transduction, yet little is understood about how these regulators control the mechanical process of morphogenesis. In order to understand the physical as well as the molecular regulators of morphogenesis we are working to "reverse-engineer" morphogenetic movements in frog embryos by applying advanced imaging, cell biological, biophysical, and bioengineering techniques at a number of different scales.

Presenter:  Marie DeFrances
Time:  12:30 pm – 1:30 pm
Location:  BST S218
Topic:  To Be Announced

Presenter:  Lance Davidson
Time:  12:30 pm – 1:30 pm
Location:  Room 1102 Scaife
Topic:  Reverse-Engineering Morphogenesis
Description: The control of morphogenesis is one of the most complex problems of modern biology and tissue engineering. Morphogenesis requires the coordination of tissue mechanics with cellular processes such as motility and shape changes. Advances have been made to understand the molecular regulation of cell motility, patterning, and signal transduction, yet little is understood about how these regulators control the mechanical process of morphogenesis. In order to understand the physical as well as the molecular regulators of morphogenesis we are working to "reverse-engineer" morphogenetic movements in frog embryos by applying advanced imaging, cell biological, biophysical, and bioengineering techniques at a number of different scales.

Presenter:  Brad Keller
Time:  12:30 pm – 1:30 pm
Location:   Room 1102 Scaife
Topic:  Insights from Embryos on the Repair of Malformed and Injured Hearts

Presenter:  Patricia Hebda
Time:  12:30 pm – 1:30 pm
Location:  Room 1102 Scaife
Topic: Inflammation and Fibrosis in Mucosal Wound Healing—Balancing the Power

Presenter:  Alan Wells
Time:  12:30 pm – 1:30 pm
Location:  Room 1104 Scaife
Topic:  From the Bed to the Bioreactor:  Tumor Cell Plasticity during Dissemination
Description:  Epithelial cadherin’s (E-cadherin) transcriptional silencing in most advanced tumors, due to promoter methylation, enables tumor cells to disseminate from the primary mass. However, E-cadherin-positive metastatic carcinoma foci do originate from mainly E-cadherin-negative primaries. It is unknown if this is due to dissemination of a minor population of E-cadherin positive cells or re-expression of E-cadherin during metastasis. Here, we demonstrate that co-culture of invasive E-cadherin-negative breast and prostate carcinoma cells with hepatocytes, the a common site of soft tissue metastasis for cancers,  triggers an epigenetic reversion in breast cancer cells resulting in demethylation of the E-cadherin promoter and subsequent expression on the protein level. This demethylation was demonstrated by methylation-specific PCR amplification. Demethylation of the E-cadherin promoter is coupled to proliferation of the cancer cells and is not the result of a global demethylation program, as inhibition of proliferation prevented re-expression of E-cadherin. We show a similar time-course for E-cadherin upregulation in 3 of 11 of primary human breast cancer explants co-cultured with primary hepatocytes.

            In both breast and prostate cancer cells, signaling through the EGFR/ErbB receptors also downregulates the E-cadherin junctions at the protein levels. Silencing of these autocrine signaling loops allows E-cadherin to then accumulate at the cell surface and form connections between cells. Initial studies suggest that this occurs via a transattenuation involving protein kinase C.

            Of greater import is the question of what advantage this re-expression of E-cadherin provides. We find that E-cadherin ligation between breast cancer cells and hepatocytes is functional and activates the canonical MAPK and Akt pathways in these cancer cells. This E-cadherin binding makes the breast cancer cells more resistant to apoptotic signals (tumor necrosis factor-alpha) and chemotherapies (camptothecin). Our epigenetic-reversion hypothesis for E-cadherin represents not only a paradigm shift in the current thinking that absence of E-cadherin is fundamental for metastasis, but also potentially reveals mechanisms underlying the failure to readily treat the early stages of metastatic disease in breast cancer patients with existing therapies.

Presenter:  Robert Kormos
Time:  12:30 pm - 1:30 pm
Location:  Room 1102 Scaife
Topic:  New technology for cardiac regenerative applications: Are pumps all we have?
Description: In past years the technology applied to devices for Regenerative Cardiac Therapy has been focused upon the replacement of Cardiac function. Heart Assist devices have matured significantly in the past 5 years to be more widely accepted for replacement, recovery and repair, however these devices still remain relatively incompatible from a biologic perspective. They are also relatively unsophisticated based upon he prejudice that they can function without feedback from the biologic arena.

A new field of sensor technology incorporating nano design and power sources with diagnostic functions needs to be developed an in fact are on the horizon.

The goal is to develop more intelligent design into these systems along with more selective applicability for specific needs.

Presenter:  To be announced
Time:  12:30 pm – 1:30 pm
Location:  Room 1102 Scaife
Topic: to be announced