Chromosome instability due to telomere loss in human embryonic stem cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00271
ICOC Funds Committed: 
$0
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Human embryonic stem cells (hESCs) have important potential in the treatment of human disease. Because they can change into a large number of different cell types, they may be useful in restoring a variety of damaged tissues. One potentially harmful side effect of hESC therapy is cancer due to unregulationed growth of the hESCs introduced in the body. hESCs have the potential to grow almost indefinitely. Therefore if they should become "transformed" into cancer cells while being cultured in the laboratory, they may cause cancer in the individuals into which they are injected. Transformation of normal cells into cancer cells can occur through changes in their DNA, which contains the information telling cells to grow or not to grow. Because multiple changes must occur for cells to begin the unchecked growth of cancer cells, the likelihood of cancer is low. However, some cellular changes can increase the rate at which subsequent changes occur, which greatly increases the probability that a cell will acquire all of the changes necessary to become a cancer cell. This increased rate of changes in DNA is called genomic instability, which is proposed to be an early step in many cancers. One mechanism by which genomic instabiiity can occur is through the loss of the caps that protect the ends of chromosomes that contain the DNA. Loss of these caps, called telomeres, can make the DNA highly unstable. This proposal will study whether the loss of telomeres is a cause of instability in hESCs during their growth in the laboratory. Information on this process will allow steps to be taken to avoid this potential harmful effect during hESC therapy.
Statement of Benefit to California: 
Human embryonic stem cells (hESCs) have important potential in the treatment of human disease. Because they can change into a large number of different cell types, they may be useful in restoring a variety of damaged tissues. This study will investigate a potentially harmful side-effect involving genetic changes that may occur during growth of hESCs in the laboratory that could lead to cancer when they are injected into people. Understanding the process involved in generating these genetic changes will allow scientists to avoid them and limit the likelihood of these complications in the clinic.
Progress Report: 
  • A promising approach to alleviating the symptoms of Parkinson's disease is to transplant healthy dopaminergic neurons into the brains of these patients. Due to the large number of transplant neurons required for each patient and the difficulty in obtaining these neurons from human tissue, the most viable transplantation strategy will utilize not fetal dopaminergic neurons but dopaminergic neurons derived from human stem cell lines. While transplantation has been promising, it has had limited success, in part due to the ability of the new neurons to find their correct targets in the brain. This incorrect targeting may be due to the lack of appropriate growth and guidance cues as well as to inflammation in the brain that occurs in response to transplantation, or to a combination of the two. Cytokines released upon inflammation can affect the ability of the new neurons to connect, and thus ultimately will affect their biological function. In out laboratory we have been examining which guidance molecules are required for proper targeting of dopaminergic neurons during normal development and have identified necessary cues. We have now extended these studies to determine that two of the molecules have dramitc effects on dopaminergic neurons made from human embryonic stem cellls and that at least in vitro, cytokines do not mask these effects. Ultimately, an understanding of how the environment of the transplanted brain influences the ability of the healthy new neurons to connect to their correct targets will lead to genetic, and/or drug-based strategies for optimizing transplantation therapy.

© 2013 California Institute for Regenerative Medicine