Fate and connectivity of HESCs in temporal lobe disorders.

Funding Type: 
SEED Grant
Grant Number: 
RS1-00434
ICOC Funds Committed: 
$0
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Public Abstract There is great promise in the use of human embryonic stem cells to treat neurodegenerative disorders. However, there are several obstacles that need to be overcome before this replacement therapy can become a reality to treat humans. The proposed research is intended to address some of the fundamental principles underlying migration of human embryonic stem cells into regions of the brain that are most vulnerable to neurodegenerative disorders, such as Alzheimer’s disease. Specifically, we intend to take advantage of an intrinsic migratory route for newborn neurons in the adult rodent brain. Our recent studies have shown that newborn neurons arise in the wall of the lateral ventricle and migrate caudally in the rat where they move into some of the cortical areas that are known to degenerate in Alzheimer’s disease. Thus, we propose experiments that will involve injections of human embryonic stem cells into the origin site of this migratory stream in adult and late-life rats, and determine whether these extrinsic cells have the capability to also migrate into these same brain areas. Because our preliminary data indicate that human embryonic stem cells migrate along this route and survive in adult rats, we plan in the proposed study to determine the rate of migration of the injected human embryonic stem cells. In addition, we propose to assess the phenotype of the migrated human embryonic stem cells in these brain areas using an assortment of labeling methods. The last experiment will be performed to determine whether the migrated cells in these brain areas establish synaptic connections with other neurons underlying their functional integration. Together these proposed studies will provide the basis for future clinical trials that are intended to use human embryonic stem cells to replace/replenish degenerating neurons in the brains of aged patients and those with Alzheimer’s disease.
Statement of Benefit to California: 
Benefit to California In the next decade, the generation of Baby Boomers will be hitting their sixties and seventies, an age when neurodegenerative diseases, such as Alzheimer’s disease, typically strike. The care and well-being of this elderly population will represent a large expense for the State of California in the near future. Therefore, the development of innovative treatments will be essential for saving health care costs for the State of California. In addition, any new treatment developed in California will directly benefit the residents by creating new jobs and keeping the state’s healthcare on the leading front of biotechnology. These discoveries made in California will lead to start-up companies creating a new economic stream by their licensing the patents generated from this research. Furthermore, California has obtained a leadership role in this field by being the first state in the USA to support Stem Cell Research. Studies such as those proposed in this grant application will lead to the use of human embryonic stem cells for replacement therapy for patients with Alzheimer’s disease. Once these treatments are developed, citizens of the USA will have to travel to California to obtain these new surgical treatments, leading to more business for the doctors and hospitals in California. In summary, California will benefit from this work through cutting edge research, better health care for its aging population, and more jobs and tax revenue resulting from the creation of these new therapies.
Progress Report: 
  • A central goal of our CIRM SEED proposal was to use innovative unbiased approaches to discover novel proteins that turn genes on or off in pluripotent stem cells. An understanding of what are these proteins that act as genetic switches and how they function is of significant importance to efforts to use pluripotent stem cells to model disease states in the lab or to provide a source of cells of therapeutic interest for transplantation. We have been successful in our efforts, in that we identified a novel protein that appears to play an unexpected role in the regulation of gene activity in pluripotent stem cells. In addition, we have identified another protein that is critical to maintain the DNA of pluripotent stem cells is a state accessible to other proteins. Our research is therefore providing an integrated picture of what are the genetic switches that turn genes on or off in pluripotent stem cells, what genes do they regulate, and how is their access to DNA regulated. Some of our results have recently been published, while other research is ongoing. In parallel, we have been very successful at transferring expertise to the biotechnology sector in California. In particular, two highly qualified lab members accepted senior scientist positions at top biotechnology firms in California (iPierian and Genentech).
  • A central goal of our CIRM SEED proposal was to use innovative approaches to discover genes that control human embryonic stem cells, with the idea that this knowledge may lead to improved methods for growth and/or differentiation of human pluripotent stem cells in a clinical setting. In the past year we have continued to make significant progress on these efforts. We have found a factor that acts to turn other genes on or off and is active in embryonic stem cells. We have put a considerable amount of effort into optimizing methods to identify exactly what genes this factor controls. Our results show that this factor directly regulates pluripotency-associated genes. This is remarkable, since this factor had not to date been implicated in the regulation of pluripotency. These results put us in a position to characterize the function of this factor in embryonic stem cells in greater detail. In addition, we are applying knowledge gained from our studies to develop methods to enhance the ease with which human pluripotent stem cells are propagated. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, are notoriously more difficult to grow than their mouse counterparts, and this has significantly hampered the ability to use existing human pluripotent stem cells to model disease. We have developed conditions that facilitate the propagation of human pluripotent stem cells in a state that resembles mouse ES cells, where they are easier to propagate and grow more rapidly. These findings, while preliminary, suggest that we have the opportunity to explore a transition of human pluripotent stem cells to a state that is easier to culture and manipulate genetically. Thus, the CIRM SEED award has allowed us to discover a novel regulator of pluripotency genes, and to develop conditions that may lead to improved culture and manipulation of human pluripotent stem cells.

© 2013 California Institute for Regenerative Medicine