Aging is an important risk factor for human diseases. In addition to cognitive decline in the elderly, brain aging also increases the risk for neurological diseases like Alzheimer’s disease (AD), Parkinson's disease (PD), and stroke, which are major causes of disability and mortality in the elderly. Current therapeutic approaches typically fail to treat the underlying cause of these disorders. The potential capacity of human neural stem cells to replace cells and tissues damaged due to aging and age-realted diseases is, therefore, of great importance. Activation or transplantation of these cells has already shown promise in animal models of these disorders. However, little is known about how aging affects host receptivity to hESC-derived cell transplants, or about the proliferation, survival, differentiation, migration and functionality of the donor cells. This is partly because in vivo studies of aged-related neurological diseases have relied almost universally on experimental models using young adult animals.We hypothesize that the ability of hESC-derived transplants to proliferate, survive, differentiate, migrate and function may be compromised in the aged brain, requiring that new strategies be devised to overcome this deficiency. The experiments we propose are designed to increase our understanding of how the age of the recipient alters the ability of transplanted neural stem cells to differentiate into mature, functional neurons and integrate into local neuronal circuits. Our first Specific Aim will examine these issues using immunocytochemistry and electrophysiological methods, after transplanting neural stem cells into young adult, middle aged and aged rats. In addition, because brain aging produces progressive changes in learning and memory, a critical area to examine is whether neural stem cell therapy can produce functional improvement in learning and memory deficits in aged rats. Our second Specific Aim will address this question by using a battery of behavioral tests to assess the ability of transplanted neural stem cells to reverse age-related losses of cognitive function. The use of neural stem cells to repair age-related neurological diseases will require an increased understanding of stem cell biology, the environment of the aged tissue, and the interaction between the two, which this proposed work will focus on. If the aims of the application are achieved, significant advances will be made in establishing a new paradigm of brain aging and the biological behaviors of transplanted neural stem cells, and substantial progress will be made in developing basic science knowledge that can be translated fairly rapidly into clinical treatment of aged-related neurological diseases.
Statement of Benefit to California:
Aging is destined to become a serious public health problem for California over the next several decades. California’s elderly population is expected to grow more than twice as fast as the total population from 1990 to 2020, and will reach 12.5 million by 2040. One in five Californians will be 60 years of age or older beginning in 2010. Consequently, age-related diseases, including neurological diseases, will dramatically increased in parallel, presenting enormous social and economic challenges. Determining whether transplanted human neural stem cells can differentiate into functional neurons in the aging brain, and thereby slow or prevent cognitive decline in the aged, could have great social and economic impact in our state.
SYNOPSIS: This proposal will study but not necessarily resolve the current dogma in the field that the 'soil' rather than the 'seed' is most important in neural stem cell transplants to an aged brain. Immunocytochemistry and patch clamp electrophysiology, along with behavioral testing, will be used to study hESC-derived neural stem cells transplanted to young adult, middle aged, and aged rat hippocampus. INNOVATION AND SIGNIFICANCE: This proposal is not particularly innovative in that there are many examples of age-related changes in the brain that affect neural stem cell transplants that have addressed the issue of an aging host brain environment and shown that is not particularly conducive for stem/progenitor cell growth and integration. What would be innovative would be to determine why this is true. There is potential significance for this study, especially if it could be determined how to prime the aged brain for receptivity to grafted hES-derived neural precursors. STRENGTHS: Most neural stem cell transplant models use young animals as recipients but this may not be the main target population for therapy. Since neurogenesis declines with age, understanding how to improve the stem cell niche in the brain (cells, extracellular matrix, soluble factors, vascular elements) might improve receptivity of grafted ES-derived cells. The current study will characterize the grafted cells in the aging niche. The suggestion that altering the cells or the aging host environment are worthy of consideration. WEAKNESSES: It is not certain that the PI and his colleagues have a great deal of experience in the directed differentiation of hESC to be able to add new and significant findings on priming these cells for the best survival and differentiation in an aged brain. This work could be done and all of the same questions answered using cells other than hESC. The PI points out that “hESC will be used for this study, because undifferentiated embryonic stem cells can proliferate indefinitely in culture…”, and even though this is true, there is a growing body of literature that suggests other cells can proliferate enough in culture to test their ability to differentiate and integrate in a hostile CNS environment. ESC studies should provide a stronger rational for usage than just being an alternative to other cells to be studied in a grafting paradigm. The PI states that “limited NIH funding available for hESC research and restricted stem cell research policy of the federal government …” would make this work “unlikely to be funded by the NIH”..; this reviewer does not believe this is true for this type of descriptive transplantation biology in aged rodent brain models, since already existing hES cell lines could be used for this type of pilot screening study. DISCUSSION: There was no discussion following reviewers' comments.