The molecular mechanism of epigenetic reprogramming by defined factors

Funding Type: 
Basic Biology I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Epigenetic reprogramming of a somatic cell into pluripotent stem cells has raised enormous interest in the scientific community because of the multitude of applications in basic biology and clinical research. Particularly important are the impacts on regenerative medicine, as reprogramming would allow the generation of patient-derived (and thus individualized) stem cells that could be used to differentiate into functional donor cells for transplantation therapies. For many years epigenetic reprogramming was only achievable in animals through somatic cell nuclear transfer (SCNT) into enucleated oocytes, a technically and logistically challenging and very inefficient procedure. To this day, epigenetic reprogramming through SCNT has not been successful in human despite great efforts. In August 2006, Shinya Yamanaka has reported for the first time that retroviral overexpression of 4 transcription factors is sufficient to induce pluripotent stem (iPS) cells from mouse fibroblasts. Similarly to the mouse cells, defined factor-induced reprogramming was then shown to work also in human cells. This paved the way for potential clinical application as for the first time patient-specific stem cells were created.

However, in both mouse and human systems the efficiency of reprogramming is extremely low. This indicates that scientists have to rely on uncontrolled events leading to reprogramming. Before we will be able to use these iPS cells in a clinical setting we will therefore have to have a much better knowledge of the reprogramming process to be able to improve the efficiency. Once we know exactly what is going on in these reprogramming cells, have absolute control over the process and can reach efficiencies close to 100%, the generation of human iPS cells from somatic cells will very likely be a safe procedure.

This research proposal addresses some fundamental questions why the reprogramming process is so inefficient. In this study we propose to optimize the expression of the reprogramming factors, to identify the best donor cell population for reprogramming, and finally to attempt to provide a list of new factors that can improve the reprogramming efficiency.

Statement of Benefit to California: 

The benefits of this research to California are two fold: 1) it stimulates the economy by directly creating 5 jobs or salary support for California citizens and supporting California business because of regular purchase of consumables and research equipment. 2) At the same time the money is spent to support a research project that aims to improve the development of a novel type of pluripotent stem cells that could be used to treat a variety of diseases such as neurodegenerative diseases, diabetes, spinal chord injury, and genetic skin and muscle diseases.

The impact of such a novel stem cell therapy on the California health system would be enormous. The number of patients suffering from neurodegenerative diseases alone are stunning: Currently 1-2% of the population older than 65 years is diagnosed with Parkinson's disease a devastating disease affecting cognition and body movements and 20% of people older than 75 years suffer from Alzheimer's disease a progredient neurodegenerative disease leading to loss of higher cognitive functions.

Any progress towards relieving the major symptoms of patients suffering from these neurodegenerative diseases will be of immense benefit to the State of California and its citizens.

In addition, all the tools and reagents that we develop will be made widely available to Californian researchers and we have selected a California-based company for potential commercialization. We hope that California-based physicians will be at the forefront of developing this promising avenue of research. We expect that the money expended on this research will benefit the Californian research community and the tools and reagents we develop will help accelerate the research of our colleagues in both California and worldwide.