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UConn Health Cell and Genome Sciences
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2006/2007 State Stem Cell Funding

Directing hES Derived Progenitor Cells into Musculoskeletal Lineages

Nine discrete projects, with grants totaling $3.5 million comprise the University’s group project, Directing hES Derived Progenitor Cells into Musculoskeletal Lineages headed by David Rowe and based at UConn Health. Collectively, the participating researchers are studying how embryonic stem cells could help rebuild bone, cartilage, skin and muscle.

Project 1: Directing ES Cells to a Common Progenitor Cell for Musculoskeletal Tissue Generation.

Alexander Lichtler, Principal Investigator, UConn Health.

The researchers are striving to develop a method that will use well-defined culture conditions to promote differentiation of human embryonic stem cells into a pure population of mesoderm cells, cells from the embryonic layer that ultimately develops into all connective tissue, muscle, bone and the urogenital and circulatory systems. Those cells would then be used by other members of the grant team to differentiate into the type of cells they are studying. Additionally, the Project 1 group will be aiding Dr. Mina (Project 6), producing embryonic stem cells equipped with fluorescent protein markers that come on when the cells have reached a certain differentiation stage.


Project 2: FACS Isolation of Progenitors and Generation Novel Cell Surfaces Antibodies.

Hector Leonardo Aguila, Principal Investigator, UConn Health.

In order for researchers to use stem cells for regenerative therapies, the design of methods for the correct identification of stem cells is crucial. One of the best approaches - not only to characterize different cell types, but also to isolate them - is the generation of antibodies against cell surface molecules. The Project 2 group has developed unique tracking systems for musculoskeletal development to visualize progenitor cells with the ability to develop into cartilage, bone, fat and muscle. These systems employ genetic techniques that add genetic information to embryonic stem cells to make them express fluorescent protein at defined stages of their development.


Project 3: Microarray.

Dong Shin, Principal Investigator, UConn.

The project focuses on state of the art microarray technology, which allows scientists to easily identify, in a single experiment, hundreds or even thousands of genes. Project 3 researchers will employ this extraordinary technology to carry out microarray experiments for the entire group, especially in support of Projects 1 and 2 and will store and manage data for analysis. The researchers will also develop a cohesive microarray data analytical framework for the group.


Project 4: Scaffolds to Hold and Mold Progenitor Cells at a Site of Tissue Regeneration.

Jon Goldberg and Liisa Kuhn, Principal Investigators, UConn Health.

Most of the projects in the grant focus on particular kinds of tissues and learning how stem cells progress toward their final tissue types, including identification of the essential “signaling molecules” that direct the cells’ development, as well as other necessary environmental factors. As those questions are answered, the knowledge will be transferred to the biomaterials scaffolds project, where methods for practical clinical application will be developed.

Traditional reparative procedures for lost or damaged limbs use prosthetics, such as the implants used in a hip or knee replacement, made of metal, ceramic and plastic biomaterials. These prostheses are meant to replace the damaged tissue or organ, not to repair it. Cell-based therapies, on the other hand, require reabsorbable biomaterials. They must carry in the cells and define and shape the area of regeneration, but they must also degrade or reabsorb so that newly grown tissues can replace them. These types of biomaterials are called scaffolds and they are porous, like sponges, so that the cells can be contained inside the pores. Their purpose is to mimic the natural environment inside the body in which cells are accustomed to living. When biomaterials are made this way, they provide a means of triggering the cell to start regenerating the lost or damaged tissue. For the stem cell project, the biomaterials group will synthesize novel scaffolds designed specifically for musculoskeletal system regeneration.


Project 5: Optimizing Mesoderm Derived Bone Cell Differentiation from hES Cells.

David Rowe, Principal Investigator, UConn Health.

The project will give researchers who have experience working with mice stem cells directed to bone cell differentiation the opportunity to apply their knowledge to human embryonic stem cells. The research aims to provide objective criteria for evaluating the potential of cells to develop in bone tissue types with the goal of maximizing the potential to efficiently differentiate cells to produce bone tissue.


Project 6: Generation of Bone via the Neural Crest Development Pathway.

Mina Mina, Principal Investigator, UConn Health.

The cells that contribute to the facial skeleton, including the bones and teeth, are formed from cells of the cranial neural crest, the part of the embryonic ectoderm that develops into the skull, spine and associated nerves. There is a significant body of scientific evidence suggesting that differences in embryonic origin and mode of ossification, the natural formation of bones, in the bones of the face, skull and spine have significant influences on various properties of the skeletal tissues at those different sites. Consequently, effective cell-based therapies for skeletal tissues in the skull and face depend upon the capacity to identify and isolate stem cells capable of appropriately regenerating skeletal tissues. Project 6 aims to develop ways to generate and identify those cells.


Project 7: Generation of Cartilage from hES Derived Progenitor Cells.

Robert A. Kosher, Principal Investigator, UConn Health.

Degenerative diseases of cartilage are among the most prevalent and debilitating chronic health problems in the United States, and one of the main causes of decreased quality of life in adults. While more than 90 percent of the population over age 40 have some form of cartilage degeneration, treatment is particularly challenging because of the limited capacity of cartilage for self-repair and renewal. Human embryonic stem cells are a potentially powerful tool for repair of cartilage defects and one of the major goals of the Project 7 team is to develop culture systems and conditions that will allow stem cells to uniformly differentiate into chrondrocytes, cells that form cartilage.


Project 8: A Mouse Model to Study the Myogenic Potential of hES Cells.

David Goldhamer, Principal Investigator, UConn.

The long-term goal of Project 8 is to develop effective cell-based therapies for muscle degenerative diseases. Toward that end, the project has three interrelated objectives: 1) to evaluate the ability of human embryonic stem cells to repair skeletal muscle, 2) to further an understanding of muscle repair by defining the functions of two key factors that regulate stem cell differentiation, and 3) to develop a new repair model, using laboratory mice, to evaluate cell-based therapeutic outcomes.


Project 9. Correction of Dermal Lesions with hES Derived Progenitor Cells.

Stephen Clark, Principal Investigator, UConn Health.

The goal of the project is to develop and test mice models utilizing human embryonic stem cells in the treatment of skin wounds. The work done in Project 9 is based on the hypothesis that embryonic stem cells can participate in and/or improve the skin wound healing process leading to a better resolution.


$2.5 Million – Human ES Cell Core at University of Connecticut and Wesleyan University.

Ren-He Xu, Principal Investigator, UConn Health.

The grant will pay for equipment for a core laboratory where stem cell lines are propagated for use by participants in all of the grants.


$880,000 – DsRNA and Epigenetic Regulation in Embryonic Stem Cells.

Gordon Carmichael, UConn Health.

Embryonic stem cells are endowed with two remarkable features. They have the capacity for self-renewal and to grow indefinitely, and they also have pluripotency, the potential to change into virtually any cell in the human body. The goals of the project are to explore the key molecular factors that govern “stemness,” and to develop technologies that will allow manipulation of stem cells and their genes.


$880,000 – Alternative Splicing in Human Embryonic Stem Cells.

Brenton Graveley, Principal Investigator, UConn Health.

In order to fully understand how human embryonic stem cells work and to develop the ability to differentiate them into specific cell types, it is essential to determine which genes and proteins are expressed in stem cells. While many studies have been conducted to clarify which genes are expressed in stem cells, all of them have overlooked an important aspect of gene expression - alternative splicing, the process by which a single gene can give rise to multiple proteins by cutting and pasting the RNA produced by the gene in different ways. The study will aim to full this research gap.


$880,000 – ChIP-Chip Analysis to Screen Target Genes of BMP and TGF Signaling in Human ES Cells.

Ren-He Xu, Principal Investigator, UConn Health.

The project extends earlier research through which two essential signaling pathways have been identified that governs the early fates of human embryonic stem cells. One of these pathways promotes the cells to differentiate, while the other sustains their self-renewal. The research will seek to identify genes that regulate both pathways.


$561,631 – Migration and Integration of Embryonic Stem Cell Derived Neurons into Cerebral Cortex.

Joseph LoTurco, Principal Investigator, Department of Physiology and Neurobiology, UConn.

The project studies the genes that control the migration of stem cell-derived neurons in the brain and will test whether some of the same proteins necessary for migration in normal brain development are also necessary for migration of transplanted stem cells. Additionally, the research focuses on ways to explore the migration of transplanted stem cells by manipulating the expression of proteins that are known to be necessary for migration in normal development.


$529,871 – Optimizing Axonal Regeneration Using a Polymer Implant Containing hESC-derived Glia.

Akiko Nishiyama, Department of Physiology and Neurobiology, UConn.

When nerve fibers are severed in the brain and spinal cord, they do not regenerate efficiently. Consequently, people who suffer damage to the brain or spine often suffer a permanent loss of function. Yet nerve fibers appear to have the potential to regenerate. Their capacity to do so is limited by environmental factors. The goal of the project is to identify methods to promote regeneration of injured nerve cells in the brain by using glial cells, cells that naturally support the health of nerves, derived from human embryonic stem cells.


$200,000 – Quantitative Analysis of Molecular Transport and Population Kinetics of Stem Cell Cultivation in a Microfluidic System.

Tai-Hsi Fan, Principal Investigator, Department of Mechanical Engineering, UConn.

Embryonic stem cells are especially sensitive to their growth environment. Maintaining them in a man-made culture medium is difficult, because the physiological conditions that can mimic the natural growth environment are not yet well developed. The project combines engineering principals with biology and analytical chemistry methods to quantify how stem cells grow and respond to environments that are physically and chemically altered. Ultimately, the team hopes to identify the ideal physiochemical conditions for the self-renewal of these cells.


$200,000 – Lineage Mapping of Early Human Embryonic Stem Cell Differentiation.

Craig Nelson, Principal Investigator, Department of Molecular and Cell Biology, UConn.

In order to use stem cells to their full potential, researchers need to be able to use them to generate medical useful cell types. However, the capacity to do this is limited by the fact that scientists actually know very little about early human embryonic development. Much of the existing knowledge has been inferred from observing the development of embryos in laboratory animals. Thus, in order to understand the behavior of stem cells in embryonic development, it is important to study that development directly. The primary objective of this project is to create a clear picture of human embryonic stem cell differentiation, a “roadmap” that will serve as a guide in the generation of the cells needed for regenerative medicine and cell replacement therapy.


$200,000 – Embryonic Stem Cell as a Universal Cancer Vaccine.

Bei Liu and Zihai Li, Principal Investigators, UConn Health.

Long before embryonic stem cells were used for genetic and developmental studies, researchers understood that the ways in which they can alter their form and replicate are similar to the ways in which cancer cells grow and proliferate. This study is grounded in the fact that immune systems can recognize antigens, such as proteins, on the surface of tumor cells that have the capacity to stimulate the production of antibodies. Most of the current research on cancer vaccines target these antigens. The researchers aim to explore the potential for using stem cells to provide a universal cell-based vaccine against cancer.


$200,000 – Generation of Insulin Producing Cells from Human Embryonic Stem Cells.

Mark Carter, Principal Investigator, Center for Regenerative Biology, UConn.

The purpose of this study is to compare mouse and human embryonic stem cells in order to better understand how stem cells can be differentiated into insulin producing beta cells. Studies in laboratory mice have demonstrated that it is possible to differentiate stem cells into insulin producing cells and restore normal insulin production once they are transplanted. The long-term goal of the study is to develop patient-specific nuclear transfer embryonic stem cells that effectively treat diabetes without immunosuppression.


$200,000 – Development of Efficient Methods for Reproducible and Inducible Transgene Expression in Human Embryonic Stem Cells.

James Li, Principal Investigator, UConn Health.

Human embryonic stem cells (hESCs) are an unlimited source of precursor cells that can be directed to differentiate into any types of cells, which can then be used for regenerative medicine and studies of toxicology and pharmacology, the studies of poisons and drugs. How quickly and how efficiently researchers will be able to use hESCs depends upon their capacity to conveniently modify the development of hESCs into various cell types as desired. Current techniques are inefficient and may produce unpredictable results that limit their utility. The purpose of this project is to use an enzyme called DNA recombinase to recognize specific DNA sequences in a specific position in the human genome and then efficiently replicate them to compel stem cells to develop according to specific requirements.


$200,000 – Pragmatic Assessment of Epigenetic Drift in Human ES Cell Lines.

Theodore Rasmussen, Principal Investigator, Department of Animal Science, UConn.

While they hold enormous promise for the future of healthcare, human embryonic stem cell lines can be very challenging to culture. They can undergo unexpected and irreversible changes that can render them useless for either therapies or further research. Reliable stem cell lines can lose their ability to form a variety of cell types or they can undergo undesirable differentiation in the course of cell culture. This study is exploring epigenetics, influences on gene expression that do not involve changes in the underlying sequence of DNA. One current theory holds that human stem cells undergo “epigenetic drift,” a poorly understood phenomenon that alters gene expression in the cells without the accumulation of DNA-based mutations. Since there is no reliable or simple method to monitor the epigenetic quality of stem cell lines, drift is usually detected only after the cells fail to perform as expected. The aim of the study is to test a new technology developed for assessing the epigenetic status of cells and, further, to try to understand why epigenetic drift occurs. If successful, the research will make the culture and maintenance of human embryonic stem cells a much more reliable process and decrease the time required to bring stem cell-based therapies to the clinic.


$200,000 – Cell Cycle and Nuclear Reprogramming by Somatic Cell Fusion.

Winfried Krueger, Principal Investigator, UConn Health.

Somatic cells, any of the cells in a plant or animal except the reproductive cells, can be reprogrammed to acquire stem cell properties by fusing them with embryonic stem cells. Nuclear reprogramming is the restoration or recreation of the correct pattern of genes in a nucleus derived from a somatic cell. However, a number of factors related to cell cycle, may impact nuclear reprogramming and significantly impact the rate of conversion of cells, depending upon what procedure is used. The project aims to examine these processes.