Evaluate Rapamycin as Powerful hESC Differentiation Tool for Pre-clinical and Clinical Application

Funding Type: 
Tools and Technologies I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Human pluripotent stem cells have already been shown to be capable of long-term self-renewal in culture and have remarkable potential to develop into many different cell types in the body (known as “pluripotency”). ). Many diseases, such as Parkinson’s disease and juvenile-onset diabetes mellitus, result from the death or dysfunction of just one or a few cell types. The replacement of those cells could offer lifelong treatment. Before the therapeutic potential of hESCs can be realized, obstacles such as the controls of their fate decisions and technical complexity to cultivate these cells must be overcome. This requires improved tools and technologies of manipulating the signaling pathways that govern hESC fate determination. Thus, it is essential to define and control these molecular mechanisms to improve conditions for synchronized hESCs for therapeutical applications. Despite recent identification of the transcriptional regulatory circuitry comprised of Sox-2, Nanog and Oct-4, the intracellular signaling networks that control pluripotency of human embryonic stem cells (hESCs) remains largely undefined. We recently discovered a known drug from a screening of chemical inhibitor collection, which can disrupt hESC pluripotency (Patent was filed). Our results have provided novel insights into the signaling mechanism by which hESCs safeguard pluripotency.

To develop this drug as powerful pharmacological tool for hESC differentiation and other stem cells, we need to evaluate it further for its irreversibility of stem cell differentiation-inducing effects and its effects for other approach-derived stem cells, such as inducible pluripotent stem cells(iPS). This discovery has provided us a powerful tool to facilitate synchronized hESC and set the stage for the induction and study of directed hESC differentiation in vivo and in vitro. Safety and immune compatibility are two critical considerations in the development of any clinical product derived from hES cells in clinics. iPS approach offers same genetic background as patients. We therefore propose to characterize the activities of this drug for its irreversibility of pluripotency blockage, its disruption of teratomas in animal implantation of hESCs and its pluripotency blockage effects in iPS. Due to small molecule properties, this drug can penetrate all hESC cells to disrupt its pluripotency in a synchronized manner, and therefore it can be used as very useful reagent to disrupt hESC teratomas in clinical transplantation therapies, and to provide large scale of synchronized human stem cells from different resources. Because this drug is currently in clinical use, our proposed experiments would allow us to verify this drug as a very useful tool for scientific research community to study signaling pathways for human stem cell pluripotency and assess the therapeutic potential in hESC preclinical models. Our research will provide a critical tool for clinical drug development for stem cell therapies.

Statement of Benefit to California: 

Human stem cells (hSCs), initially derived from embryos or recently derived from somatic nuclear transfer and combinatorial gene expression, represent a inexhaustible source of precursor cells to treat degenerative, malignant, or genetic diseases, or injury due to inflammation, infection, and trauma. This pluripotent cell has been hailed as a possible means for treating Parkinson’s disease, Alzheimer’s, diabetes, spinal cord injury, heart failure, and bone marrow failure. Meanwhile, hSCs are an invaluable research tool to study human development, both normal and abnormal, and can serve as a platform to develop and test new drugs.

The drug that can disrupt pluripotency of human stem cells will unlock whole new techniques for working with these valuable but sophisticated resources. The proposed project, when successful and scaled up, eventually will serve to disrupt pluripotency of a variety of stem cell types as used in many downstream medical, biotechnology and pharmaceutical projects. A ready source of conveniently available stem cells of all types, in turn, will act as a catalyst for new fundamental discoveries in stem cell biology, and will provide enabling reagents for many future products and methods. These discoveries, products, and methods will improve the tax base, create many new jobs, and save billions in healthcare costs in California.

Product resulting from this project will lead to a quick development of powerful scientific tool and drug for stem research and clinic application for stem cell therapy. Improved function in patients afflicted with these diseases will greatly promote the public health and result in tremendous savings to California in healthcare costs, particularly in the areas of long-term care. Federal constraints on stem cell research create a critical need for non-federal funds to achieve these goals. Funding by the California Institute for Regenerative Medicine improve California’s stem cell infrastructure and speed the translation of basic university research into medical products that change lives in the nearly future.

Stem cell technology is currently a very strong research area where rapid advances are possible and the research in developing new products and unlocking basic understanding of how human cells function is of very high value. California has initiated the largest efforts in stem cell research in the world. Therefore, California is viewed as a world leader in stem cell research, biotechnology and pharmaceutical research and development, and the advances in the field made here will contribute to the California’s leading position in these fields immediately.