Anesthetic Effects on Neural Stem Cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00298
ICOC Funds Committed: 
$0
Disease Focus: 
Cancer
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
The long-term objectives of this research are to identify safe and effective anesthetics to be used for human stem cell transplantation and to define the effect anesthetics have on stem cells in vivo. To achieve this goal we will identify the effect of several common anesthetic drugs on stem cells in culture and in animals. Specifically, we will determine whether anesthetics change the rate of growth of stem cells or limit the type of cell they may eventually become.
Statement of Benefit to California: 
Human embryonic stem cell based therapies will likely be attempted for multiple diseases in many different organ systems in the next few decades. Stem cell transplant in humans and experimentation in animal models will require sedation or complete general anesthesia for many therapies. Very little research has been done on the role that common anesthetics may play in the biology of human stem cells, and how such anesthetics may affect the function or differentiation of these cells once transplanted. Choosing the correct anesthetic may impact the success or failure of early animal and human clinical trials. This proposal focuses specifically on neural stem cells which have been proposed as a potential treatment for many different pathologic states including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, spinal cord injury and traumatic brain injury. Some stem cell transplants will be performed under general anesthesia and some will be performed in individuals likely to undergo multiple or long duration anesthetics around the time of their injury and potential transplant (i.e. traumatic brain injury, spinal cord injury, and neonatal stroke) leading to more anesthetic exposure after the transplant. Understanding the role of anesthetics in stem cell biology is imperative and will provide the basis for developing appropriate anesthetic techniques for stem cell based clinical applications.
Progress Report: 
  • Human embryonic stem cells (hESCs) hold promise for treating a broad range of human diseases. However, at the time when we submitted this proposal, there was a striking paucity of published studies on how the fate of hESCs is controlled. For instance, we know that hESCs can form tumors upon transplantation, but the mechanisms governing cell division in these cells were still largely unknown. Given the central role of the retinoblastoma (RB) family of genes at the interface between proliferation and differentiation, our goal was to study the function of RB and its family members p107 and p130 in human embryonic stem cells (hESCs). In the last two years, we have examined the consequences of altering the function of RB, p107, and p130 for the proliferation, self-renewal, and differentiation potential of hESCs.
  • We have found that overexpression of RB results in cell cycle arrest in hESC populations, indicating that the RB pathway can be functionally activated in these cells. We have also found that loss of RB function does not result in significant changes in the biology of hESCs. In contrast, inactivation of several RB family members at the same time leads to self-renewal, proliferation, and differentiation defects.
  • Together, these studies indicate that the level of activity of the RB family is critical in hESCs: too much or too little RB family function results in loss of proliferative potential.
  • Our future goal is to precisely manipulate the levels of RB family genes to determine if we can identify conditions to manipulate the fate of hESCs, reducing their ability to proliferate (suppressing cancer) while allowing them to differentiate into specific lineages.

© 2013 California Institute for Regenerative Medicine