The promise of human embryonic stem (ES) cells is that their use could revolutionize the treatment of many human diseases for which current treatments are ineffective. Many interventional therapies will rely on the manipulation of stem cell differentiation in order to selectively produce a particular cell or tissue type. To accomplish this, we will first need to increase our understanding of lineage commitment during early embryogenesis, and define how, once cells have differentiated into a particular cell type, organogenesis is regulated, i.e. how the movement and organization of cells is controlled. During embryogenesis, cells can move in ways that are very similar to the movement of cancer cells during metastasis. That is, cells have the ability to both migrate on and degrade a mixture of proteins called extracellular matrix (ECM). An example is heart formation, where the coordinated movement of the cells that make up the cardiac crescent is followed by reorganization and differentiation, including the invasion of cardiac progenitors into the cardiac jelly (ECM) to form the valves. Our hypothesis is that the same mechanisms are used to control invasive movements during early embryogenesis and metastasis. In support of this hypothesis, we have recently found that some of the cells present in embryoid bodies (cultures of differentiated cells derived from human ES cells) express genes and contain cell structures that are found in metastatic cancer cells. In particular, genes called Tks4 and Tks5 are selectively expressed in some cells. Furthermore, our preliminary experiments with zebrafish embryos have revealed that loss of Tks4 and Tks5 leads to very early severe developmental defects, consistent with loss of cell movements. Our goal here is to dissect the control and function of Tks4 and Tks5 during early development of human ES cells in culture. Understanding the mechanisms by which movement and ECM degradation is controlled during early human embryogenesis will set the stage for determining how to manipulate these properties in the future.
Statement of Benefit to California:
Each year large numbers of Californians are afflicted by diseases such as Parkinson's, Alzheimer's, and diabetes. Stem cell therapies may revolutionize how these diseases are treated in the future. For this revolution to occur, we will need to accomplish a number of goals. For example, for each disease to be treated, we will need to be able to produce the correct type of cell or progenitor (eg neuronal cell, pancreatic beta-cell), and deliver it to the patient so that it will function correctly. In some cases, we may also want to be able to control the movement of the cells, either promoting their migration or ensuring that they cannot migrate, depending on the disease to be treated, and the way in which the cells are to be delivered. The research proposed here is part of an overall effort to understand how the movement and development of human embryonic stem cells and the more differentiated progenitors that arise from ES cells are controlled. With this knowledge, we may in the future be better able to harness stem cell therapies.