Characterizing the Molecular Mechanisms of Pluripotent Stem Cell Self-Renewal
Human pluripotent stem cells (PSC) have the potential to produce all of the different cells in the human body. There are many studies using human PSC to develop new therapies for patients with genetic disease, birth defects or injuries. One obstacle to the development of these stem cell therapies is that very often human PSC randomly differentiate (or change) into non-specific cell types in the laboratory. When the cells randomly differentiate they can not be used to make the cells or tissues of interest. It’s not clear how to prevent this random differentiation because at this time we do not completely understand the biology of these human stem cells and what factors keep them alive and expanding. A second problem with current stem cell research is that the most reliable method to keep the human stem cells alive and expanding is to culture them on cells obtained from mice. This culture with animal cells makes the currently available human stem cells unsafe for use in patients. The overall goal of these studies is the development of safe methods to produce human stem cells to make cells and tissues for patients.
We are developing a completely new approach to keep human stem cells growing. We are developing a synthetic material based on a normal human protein that is known to be required for human stem cells to survive and expand without differentiation. Excitingly, our preliminary studies demonstrate that by adding our material, we can keep stem cells alive, and undifferentiated for at least three days (the longest time evaluated). The goal of these studies is to continue and further study our new approach, and evaluate its potential to maintain stem cell survival and growth. We will also study the genes and proteins involved in normal human stem cell survival, to learn more about the biology of these cells, and optimize the development of materials for maintaining human stem cell survival and expansion for clinical applications.
If successful, the development of such synthetic materials that maintain the undifferentiated state of stem cells will make all aspects of human stem cell research more reliable and efficient. This in turn will increase the time that researchers have to developing therapeutic protocols, rather than spending a large amount of their time and energy to keep their cells alive and renewing. Furthermore, it will facilitate the scale-up of stem cell applications from small-scale laboratory studies. Thus, our studies have the potential to impact on all human stem cell research, and increase the rate of development of all stem cell based therapies. The development of a safe, synthetic material that can replace mouse cells, and reliably keep the stem cells alive would prove very useful to stem cell researchers, as well as increase the safety of the cultures for therapeutic purposes.
One of the biggest hurdles in human stem cell research is that in the laboratory, the cells spontaneously and randomly change into a variety of cell types in culture by a process called differentiation. Cells that have undergone uncontrolled differentiation can not be used to make cells or tissues for use in patients. A high degree of technical training can reduce this random differentiation, but it is not preventable with currently available techniques to grow stem cells. Our project will study the biological processes that keep stem cells renewing and expanding. We will then use this information to develop new materials that can be added to cells in the laboratory to keep stem cells growing in an undifferentiated state - so that they can better be used to make cells and tissues for clinical applications. If successful, these materials will increase the efficiency of all human stem cell research, by dramatically decreasing the amount of time spent researchers spend keeping human stem cells alive and undifferentiated. In turn, this will allow researchers to spend more time and effort developing stem cell therapies for human disease. Finally, since our material will be made in a laboratory using safe procedures, it will also increase the safety of the stem cells used to make cells and tissues for patients, by reducing the need for animal or human products in the system.