Derivation of Customized Stem Cells for Regenerative Medical Therapy

Funding Type: 
SEED Grant
Grant Number: 
RS1-00249
ICOC Funds Committed: 
$0
Disease Focus: 
Solid Tumor
Cancer
Pediatrics
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Embryonic stem cells hold great promise in regenerative medicine for the treatment of numerous diseases, injuries, and disabilities. Despite recent clinical successes, there remain significant hurdles to establishing ethically sound, scientifically feasible, and practically realistic human stem cells that engender broad public support and exhibit convincing therapeutic effectiveness. Among these hurdles are the source (embryo vs adult) of stem cells and immune rejection following transplantation. To overcome these two hurdles, our long-term goal is to develop and apply efficient technologies for deriving pluripotent, embryonic-like stem cells from a patient's own tissues for the purpose of providing "customized", patient-specific regenerative therapy. The rationale behind our long-term goal is that the destruction of human embryos to derive new embryonic stem cell lines, and the clinical complications associated with rejection of transplanted stem cells that are not recognized as "self", prevent full realization of the enormous potential of regenerative therapies using stem cells. Therefore, the overall objective of this SEED grant, which is the first step in achieving our long-term goal, is to extend and enhance existing technology for efficiently and reliably using adult human somatic cell nuclei to derive pure, pluripotent human embryonic-like stem cells. Our central hypothesis is that customized and therapeutically-useful embryonic-like stem cells can be derived from adult, human fibroblast nuclei reprogrammed in mouse oocytes. The justification for this project is that this methodology would eliminate the creation and/or destruction of human oocytes and embryos to derive patient-specific embryonic-like stem cells, preclude the need for immunosuppresvie therapy in patients receiving stem cells, and allow for the possibility of correcting inherited genetic mutations.
Statement of Benefit to California: 
The research proposed here will significantly advance the field of stem cell biology, thereby promoting translational research applications that drive achievements of basic research to the patient's bedside faster and more effectively than before. By doing so, and by improving the health of the citizenry in need of regenerative medicine using stem cells, then this project will be of benefit to the State of California. In addition, this area of research will attract a broader and more diverse array of scientific experts in the field of stem cell biology to California, thereby also contributing to the advancement and development of the State's biomedical research enterprise.
Progress Report: 
  • Recent studies have shown that mutations in the DNA of adult stem cells can lead to the formation of cancerous rather than normal tissues. However, with the exception of blood, adult stem cells are rare and not readily accessible for isolation or study. Thus, very little is yet known about how these stem cells are hijacked to cause cancer.
  • Our laboratory is studying how mutations in stem cells give rise to Ewing sarcoma. Ewing sarcoma family tumors (ESFT) are highly aggressive tumors that primarily affect children and young adults. ESFT have a specific mutation in their DNA that leads to the creation of a cancer-causing gene called EWS-FLI1. It is our hypothesis that expression of EWS-FLI1 in adult stem cells generates ESFT. In particular, we are interested in a very rare population of adult stem cells called neural crest stem cells (NCSC) and these cells have been the focus of our CIRM-funded grant.
  • We initially proposed that human embryonic stem cells (hESC) could be used to generate NCSC and that these cells would be invaluable tools with which to study the origin of ESFT. In the first year of the grant we successfully achieved this goal and the work has been published. In the second year of the grant we have studied the consequences of activating the EWS-FLI1 on these cells. Importantly, our work shows that NCSC that express EWS-FLI1 do not differentiate normally. Instead they acquire properties of cancer stem cells. Thus, we propose that ESFT arise from NCSC that acquire a genetic mutation that prevents them from developing normally. These abnormal stem cells then go on to develop into full blown tumors.
  • By creating novel stem cell models to study the origin of ESFT we are gaining new insights into how these tumors arise in children. These insights will ultimately aid in the development of more effective therapies that can be designed to destroy abnormal cancer-causing stem cells whilst sparing normal stem cells.

© 2013 California Institute for Regenerative Medicine