Circuitry of Cell Cycle Control in Human Pluripotent Stem Cells
Human pluripotent stem cells such as embryonic and induced pluripotent stem cells have the ability to grow to unlimited numbers while retaining the potential to differentiate into all tissue and cell types of the human body. This is potentially a great advantage for transplantation medicine, because cell grafts typically require large numbers of cells. Candidate diseases for cell transplantation therapies typically have progressive loss of specific cell types. Those include diabetes, coronary heart disease, Alzheimer’s, Parkinson’s and many others. In addition, acute damage due to injuries such as spinal nerve damage are likely to be more readily healed in the future if cells can be stimulated to carry out repair processes. The idea is to differentiate large amounts of pluripotent stem cells into a specialized cell type that is lost in a particular disease or injury – such as neurons, heart muscle cells or pancreatic cells – and use those cell populations to graft into patients. Such an approach requires that the cells grow when needed, but then they must cease growing and persist as healthy parts of new tissue. Undifferentiated stem cells that persist after transplantation might continue growing uncontrollably, which can lead to cancer. Even minimal numbers of undifferentiated cells, implanted into host tissue, can form tumors. Therefore, it is essential to gain control over growth regulation of pluripotent stem cells. Ideally, research will succeed in inventing ways to modify pluripotent stem cells to eliminate their tumor-potential, without compromising their initial growth or their potential to give rise to many specialized cell types.
In the planned experiments we will characterize the growth control systems of human embryonic and induced pluripotent stem cells. These cells have remarkable properties that are different from most cell types that have been studied before—different proteins are important in human stem cells for growth control. We have developed imaging technologies that allow sensing of the different growth stages in living human stem cells. With these new tools we will identify key genetic factors that regulate the progression of cell division. Typically, cells have several control mechanisms and checkpoints that regulate cell division. The unique attributes of human stem cell division controls are the reason they can grow into tumors when implanted. We hypothesize that the introduction of more cell cycle regulators and checkpoints will reduce or perhaps even eliminate the cancer forming ability of these cells. That sort of engineering is possible, for example with drugs or genetic engineering of cells, once we understand how the cell division regulators work. The goal of the planned experiments is to provide detailed information which will lay the foundation for developing ways to better regulate cell growth of pluripotent stem cells and minimize the risk of cancer formation following transplantation.
The people of California voted for Proposition 71 to provide substantial support for research that leads to the development of human pluripotent stem cell therapies. The first human stem cell trials are being initiated and there is huge excitement about their therapeutic potential. The people of California have seen the practical benefits of creative high technology industry in computers, drug discovery, energy, and media, and would like to lead the world again in medicine that takes advantage of new technology. California is a natural home for the regenerative medicine revolution, due to its concentration of leading universities and the computational and financial infrastructure that will allow rapid capitalization of new technologies. Should pluripotent stem cells indeed find their way into the clinics the benefit would be for those patients suffering from diseases that can be treated with stem cell approaches; a vast population of potential beneficiaries lives in California. Over 1.8 million people in California have diabetes alone, and many of them have lost the cells that would normally produce insulin. Since the new therapies will employ implants, the State will directly benefit from having local in-state scientific expertise working closely with clinicians at local treatment centers. The potential diseases that could be good candidates for treatment include but are not limited to the major neurodegenerative diseases like Parkinson’s disease, Huntington’s disease, and possibly Alzheimer’s disease as well as diseases with tissue loss in other organs such as heart diseases, diabetes, chronic inflammations, and perhaps even cancer. The therapies are also likely to be applicable to injuries such as bone breaks, cartilage loss, and spinal neuron damage.
Obviously, the prerequisite for any of these potential cell therapies is that the cell grafts are safe and that the transplanted stem cells do not cause cancer. Unfortunately, the very nature of the undifferentiated pluripotent stem cells is that they behave like cancer cells and can form tumors that pathologists know as teratomas. Therefore, a key requirement for any cell population that will be grafted is that we eliminate the cancerous properties of these cells before we implant them. The work proposed in this application will provide detailed mechanistic insights into the regulation of the cancer-causing growth properties of pluripotent stem cells. Our studies of cell division controls and how to manipulate them will be a basis for the ultimate goal of this project, which is to minimize the cancer properties of the cells by engineering or modifying existing stem cell lines.
In summary, our research will provide ways to make human pluripotent stem cell lines safer for any kind of transplantation therapy. This will benefit every patient receiving potential stem cell grafts in the future, including the many Californian patients that could benefit from with such a therapy.