Day 2

Tuesday, August 15

STEM CELLS AND THERAPEUTICS

7:30am Breakfast Workshops (Sponsorships Available)

8:15 Chair's Remarks

Plenary Keynote Presentations
	8:25 Certain Aspects of Neural Stem Cell Biology May Suit for CNS Restoration Evan Y. Snyder, MD, Ph.D., Professor & Director, Stem Cell & Regeneration Program, Program in Developmental & Regenerative Cell Biology, The Burnham Institute An intriguing phenomenon with possible therapeutic dividends has begun to emerge our observations of the behavior of neural stem cell (NSC) clones in various mouse primate models of CNS injury and degeneration. During phases of active neurodegeneration, factors seem to be transiently elaborated to which NSCs may respond by migrating long distances) to degenerating regions & attempting to restore homeostasis. This include differentiating towards the replacement of degenerating neural cells of types, not only neurons but also requisite non-neuronal "chaperone" cells, all of which essential for the proper development and reconstitution of function. These "repair mechanisms" may reflect the re-expression of basic developmental programs (particularly temporal "windows" following injury) that may be harnessed for therapeutic ends.
	9:05 Tissue Engineering Based on Muscle-Derived Stem Cells: Potential Applications for Tissue Regeneration Johnny Huard, Ph.D., Henry J. Mankin Professor, Department of Orthopaedic Surgery Molecular Genetics and Biochemistry and Bioengineering and Director, Stem Cell Research Center, Children's Hospital of Pittsburgh   Muscle-derived stem cells (MDSCs) exhibit long-term proliferation and high self-renewal rates and can differentiate toward various lineages, both in vitro and in vivo. The transplantation of MDSCs, in contrast to that of other myogenic cells, has improved the efficiency of dystrophic muscle regeneration and the delivery of dystrophin to dystrophic muscle. Recent studies performed by members of my laboratory have shown that transplantation of female MDSCs (F-FMSCs) rather than male MDSCs (M-MDSCs) significantly improves skeletal muscle regeneration despite the similar myogenic and stem cell marker expression by both cell types. This presentation will explain the increased muscle regeneration efficiency exhibited by F-MDSCs and will also address the influence of environmental cues within dystrophic or injured skeletal muscle on the differentiation of MDSCs into fibrotic cells. I will discuss potential strategies by which to prevent scar tissue formation within injured muscle by blocking TGF-â1 activity. I then will discuss the use of MDSCs in gene therapy and tissue engineering applications designed to improve bone and articular cartilage healing through the genetic modification of MDSCs to express osteogenic proteins (BMP2 and -4) and the angiogenic factor VEGF. I will also outline in my presentation new results obtained with human muscle derived stem cells, which we believe will open new avenues by which researchers could use muscle stem cell-based gene therapy and tissue engineering to improve tissue regeneration.
	9:50 Funding and Commercializing Cellular Therapeutics Jim Sherblom, M.B.A., Managing General Partner, Seaflower Ventures Cellular based therapies including those derived from stem cells have the potential to provide effective treatments for regeneration of damaged or diseased tissues or organ systems. There's the money! However, the challenge of drawing upon the available scientific evidence to gauge safety is only one obstacle in commercial development. Cell therapies also present unique challenges in patents, process development, characterization, GMP and GTP manufacturing, and distribution. Where's the money? This presentation utilizes expertise from twelve years in venture capital and commercial experience at Genzyme and Transgenic Sciences, Inc. to determine - how to get the money.

10:30 Refreshment Break, Poster and Exhibit Viewing

EXPLORING ALTERNATIVE THERAPEUTICS

11:30 Mesenchymal Stem Cells as Multidrug Delivery Systems
Arnold I. Caplan, Ph.D., Professor of Biology, Professor of General Medical Sciences, Case Western Reserve University
Adult Mesenchymal Stem Cells (MSCs) are capable of differentiating into bone, cartilage, muscle, marrow stroma, ligament/tendon, fat and other connective tissue. Importantly, MSCs themselves secrete an array of bioactive agents that have therapeutic ("trophic") effects on injured/regenerating tissue. These MSCs secreted agents are anti-scarring, anti-apoptotic, angiogenetic, and mitotic for tissue-specific (intrinsic) stem cells. Thus, MSCs must be viewed as regulated multi-drug delivery vehicles.

12:00 Can We Make Pluripotent Stem Cells without Using Embryos
Tanja Dominko, Ph.D., CSO, CellThera Inc.
The key to the replacement of lost body parts in humans, whether by tissue engineering or by inducing regeneration, lies in identifying the regeneration-inducing signals in cells that retain their pluripotent characteristics. Examples of such cells include female gametes. Extract from
Xenopus laevis (frog) eggs has been used extensively in the past to characterize molecular events regulating nuclear remodeling, an event prerequisite for re-programming of differentiated nuclei. Characterization of Xenopus extract components that are responsible for regulation of these complex events would allow for de-differentiation of adult somatic cells in vitro into a pluripotent, blastema like state. These cells can then in turn be induced once again to recapitulate embryonic developmental processes. If placed at a site of injury, or their de-differentiation induced at the site of injury, these cells could have the potential to regenerate the lost tissues while maintaining the correct spatial and temporal relationships between them.

12:30 Lunch Break - Technology Workshops (Sponsorships Available)

THERAPEUTICS

2:00 Chair's Remarks

2:05 Cerebral Ischemia
Jenny Wu, Ph.D., Senior Research Scientist, Cardiovascular Medicine, Stanford University
Stroke is a leading cause of death and disability, but despite intensive research, few treatment options exist. Preliminary observations suggest that cell transplantation may be a viable stroke therapy. We transplanted genetically modified ESC-derived endothelial cells to a rat MACO model. We traced these transplanted cells with molecular imaging and found these cells mobilized,
integrated into the ischemia injured region. It reconstituted the complex of neuronalendothelial interrelationships through revascularization and promoted functional recovery.

2:35 Stem Cells Repair Damaged Islet in Vitro
Luguang Luo, Ph.D., Assistant Professor, Research, Stem Cell Center, Roger Williams Hospital
The restoration of pancreatic endocrine function in type 1 diabetic patients has recently been shown to be possible through pancreatic islet transplantation. However, the high rate of islet cell death and dysfunction after isolation means that a large amount of pancreatic ß cells are required to enable a single patient to be insulin independent. Thus, this therapeutic option is limited for the majority of type 1 diabetic patients. Restoring pancreatic islet function following the isolation process will be critical if such transplants are to be more widely available.
Given recent evidence that bone marrow stem cells have demonstrated promise in healing nervous, heart, and muscle tissues, we hypothesized that bone marrow cells could provide similar advantages for islets. In this lecture, we will introduce the first evidence, the possibility of allogeneic bone marrow repairing islet injury in vitro and provide repairing process by Time Lapse Microscopy Technology. Islets repaired by allogeneic bone marrow (3-week co-cultured) proved to be far superior in recovering hypoglycemia in Non-Obese Diabetic Severe Combined
Immunodeficiency Disease (NOD/SCID) mice than three-week cultures of islets only.

3:05 Technology Watch (Sponsorships Available)

3:35 Refreshment Break, Poster and Exhibit Viewing

4:15 Recovery from Paralysis in Adult Rats using Embryonic Stem Cells
Deepa M. Deshpande, Research Technician, Department of Neurology, Johns Hopkins University School of Medicine
We explored the potential of embryonic stem cell-derived motor neurons to functionally replace those cells destroyed in paralyzed adult rats. We administered a phosphodiesterase type 4 inhibitor and dibutyrylcyclic adenosine monophosphate to overcome myelin-mediated repulsion and provided glial cell-derived neurotrophic factor within the sciatic nerve to attract transplanted embryonic stem cell-derived axons toward skeletal muscle targets. We found that these strategies significantly increased the success of transplanted axons extending out of the spinal cord into ventral roots. Furthermore, transplant-derived axons reached muscle, formed neuromuscular junctions, were physiologically active, and mediated partial recovery from paralysis. We conclude that restoration of functional motor units by embryonic stem cells is possible and represents a potential therapeutic strategy for patients with paralysis. This is the first report of the anatomical and functional replacement of a motor neuron circuit within the adult mammalian host.

4:45 Pluripotent Stem Cell Treatment of Ischemic Cardiovascular Injury
Robert J. Deans, Ph.D., Vice President, Regenerative Medicine, Athersys, Inc.
Pluripotent stem cells from bone marrow have promise for treatment of ischemic cardiovascular injury not only through demonstrated trophic influences, but also possibly through stimulation and participation in tissue repair. Using both allogeneic and xenogeneic stem cell treatments in rat and pig acute myocardial infarct models, strong performance improvements are correlated with retention of cells and localization throughout the scar and peri-infarct zone.  Benefit and cell retention is equivalent with or without immunosuppression, establishing a strategy for allogeneic cell treatment. Discussion will focus on dosing and catheter delivery routes as key pre-clinical parameters for clinical trial design.

5:15 Multimechanistic Repair of Injured Spinal Cord: Stem Cell and Material
Science
Yang (Ted) D. Teng, Ph.D., Associate Professor of Surgery, Physical Medicine & Rehabilitation, Harvard Medical School
We've demonstrated that biodegradable scaffolds impregnated with murine or human NSCs appeared to enhance donor cell survival, to modify host microenvironment via milieu of donor host molecular interactions, and to consequently bridge great gaps in infarcted parenchyma by promoting outgrowth/ingrowth of donor/host fibers. Such findings indicate powerful reciprocal relationships between the injured host, stem cells, and the biomaterial. Within the spinal cord, the combination of NSCs on such a scaffold helped enunciate the effective influence NSCs may actually have on "jump starting" intrinsic regenerative and/or neuroplasticity mechanisms within the host. In summary, our results elucidate the fact that intelligent application of NSCs
for therapeutic purposes demands in-depth understanding of the cellular and molecular principles underlying the interactions among the host, the donor NSCs, and the targeted pathophysiology. Since NSCs are essentially the first stem cell isolated from a solid organ, their use for repair in prototypical brain and spinal cord injuries may help establish paradigms for stem cellbased reconstructive strategies in other solid organs.

5:45 Close of Day