Molecular mechanisms involved in adult neural stem cell maintenance

Molecular mechanisms involved in adult neural stem cell maintenance

Funding Type: 
New Faculty I
Grant Number: 
RN1-00527
Award Value: 
$2,348,435
Disease Focus: 
Aging
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
Cell Line Generation: 
Adult Stem Cell
Status: 
Closed
Public Abstract: 
The adult brain contains a pool of stem cells, termed adult neural stem cells, that could be used for regenerative purposes in diseases that affect the nervous system. The goal of this proposal is to understand the mechanisms that promote the maintenance of adult neural stem cells as an organism ages. Understanding the factors that maintain the pool of adult neural stem cells should open new avenues to prevent age-dependent decline in brain functions and to use these cells for therapeutic purposes in neurological and neurodegenerative diseases, such as Alzheimer’s or Parkinson’s diseases. Our general strategy is to use genes that play a central role in organismal aging as we have recently discovered that two of these genes, Foxo and Sirt1, have profound effects on the maintenance and self-renewal of adult neural stem cells. We propose to use these genes as a molecular handle to understand the mechanisms of maintenance of neural stem cells. Harnessing the regenerative power of stem cells by acting on genes that govern aging will provide a novel angle to identify stem cell therapeutics for neurological and neurodegenerative diseases, most of which are age-dependent.
Statement of Benefit to California: 
As the population of the State of California ages, neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease affect increasing numbers of patients. There are no efficient treatments of cures for these diseases. In addition to the devastating effects of neurodegenerative diseases on the patients and their relatives, the cost of caring for California’s Alzheimer patients—about $22.4 billion in 2000—has been estimated to triple by 2040 due to the aging of the baby-boomer’s generation. Stem cells from the brain, or neural stem cells, hold the promise of treatments and cures for these neurodegenerative diseases. One therapeutic strategy will be to replace degenerating cells in patients with stem cells. Another approach would be to identify strategy to better maintain the pool of neural stem cell with age. Both approaches will only be possible when the mechanisms controlling the maintenance of these stem cells and their capacity to produce their functional progeny are better understood in young and old individuals. We propose to study the mode of action in neural stem cells of two genes, Foxo and Sirt, that are known to play major roles to extend lifespan in a variety of species. These genes are major targets for the development of stem cell therapeutic strategies that will benefit a wide range of patients suffering from age-dependent neurodegenerative disorders. The development of effective replacement therapies in neurodegenerative diseases will be a benefit for the rapidly aging population of California; it will also alleviate the financial burden that these age-related disorders create for the State of California.
Progress Report: 

Year 1

Aging is accompanied by a decline in the number and the function of adult stem cells in several tissues. In the brain, the depletion of adult neural stem cells (NSC) may underlie impaired cognitive performance associated with aging. Discovering the factors that govern the maintenance of adult NSC during aging should allow us to harness their regenerative potential for therapeutic purposes during normal aging and age-related neurodegenerative disorders. We have recently found that two 'longevity genes', Foxo3 and Sirt1, are critical for adult NSC function. In the past year, we have published a manuscript showing that Foxo3 is necessary for the maintenance of NSC in the adult brain. We have also started to explore the critical mechanisms by which Foxo3 maintains adult neural stem cells in the brain. We have used ultra-high throughput sequencing approach to reveal that Foxo3 is recruited to the regulatory regions of 3,000 genes in the adult neural stem cells, thereby triggering a gene expression network that regulates both the ability of neural stem cells to divide and their ability to give rise to progeny. Finally, we have obtained new results in the past year, showing that Sirt1, another 'longevity gene' is critical for the proper function of neural stem cells in the adult brain, and their ability to give rise to differentiated cells. Together, our results will help understand the regulation of neural stem cell maintenance in aging individuals and will provide new avenues to preserve the pool of these cells in the brain. Modulating longevity genes to harness the regenerative power of stem cells will provide new avenues for stem cell therapeutics for neurological and neurodegenerative diseases, most of which are age-dependent.

Year 2

The adult brain contains pools of stem cells called neural stem cells that are critical for the formation of new neurons in the adult brain. During aging, the number of neural stem cells and their ability to give rise to new neurons strikingly decline. This decline could underlie at least in part memory deterioration that occurs during aging and age-related neurodegenerative disease such as Alzheimer’s disease. We have been interested over the years in the importance of genes that regulate overall longevity in the control of the pool of neural stem cells. We made the important discovery that Foxo3, a gene that has been implicated in human exceptional longevity, is necessary for preserving the neural stem cell pool. In the past year, we have made extensive progress in characterizing the ensemble of genes regulated by Foxo3 in adult neural stem cells, a key step in unraveling the mechanisms by which neural stem cells are maintained intact. In the past year, we have observed that in the absence of another gene important for longevity Sirt1, there is an unexpected increase in oligodendrocyte progenitors, which are cells that are important for myelination of neurons, which is important for the proper propagation of the neuronal information. Defects in myelination, which happen for example in multiple sclerosis, have devastating consequences on the neurological function. In the past year, we have made progress to understand the cellular and molecular mechanism of action that enhances the production of oligodendrocytes in the absence of Sirt1. Finally, we have made progress in initiating a project in human stem cells that can be reprogrammed from adult cells, to extend our findings from mice to humans, in particular as it relates to human diseases that have an age-dependent component.

Year 3

The number and function of adult stem cells decrease with age in a number of tissues. In the nervous system, the depletion of functional adult neural stem cells (NSC) may be responsible for impaired cognitive performance associated with normal or pathological aging. Understanding the factors that govern the maintenance of adult NSC should provide insights into their regenerative potential and open new avenues to use these cells for therapeutic purposes during normal aging and age-related neurodegenerative disorders. Clues to key regulators of stem cell functions may come from studies of the genetics of aging, as genes that regulate longevity may do so by maintaining stem cells. To date, the most compelling examples for genes that control aging in a variety of organisms include the insulin-Akt-Foxo transcription factor pathway and the Sirt deacetylases. We have recently found that Foxo3 regulates a network of genes in adult NSC and interact with another transcription factor, called Ascl1, to preserve the integrity of the NSC pool and prevent the premature exhaustion of this important pool of cells. In the past year, we have also made the surprising discovery that inactivating Sirt1 in adult neural stem cells leads to the increased production of oligodendrocyte progenitors, which are cells that are crucial for myelination and could help demyelinating diseases, such as multiple sclerosis, or demyeliating injuries such as spinal cord injuries. Importantly, the enzymatic activity of Sirt1 can be targeted by small molecules, underscoring the potential for Sirt1 as a therapeutic target in stem cell and oligodendrocyte production. In the last year, we have also made significant progress in using cellular reprogramming to investigate the role of longevity genes in human cells. Our work examines the mechanisms by which ‘longevity genes’ regulate stem cell function and maintenance. Harnessing the regenerative power of stem cells by acting on longevity genes will provide a novel angle to identify stem cell therapeutics for regenerative medicine.

Year 4

The adult brain contains reservoirs of neural stem cells that are critical for the formation of new neurons, oligodendrocytes, and astrocytes in the adult brain. During aging, the number of neural stem cells and their ability to give rise to new neurons strikingly decline. This decline could underlie at least in part the decline in memory that occurs during aging. We are interested in the importance of genes that regulate organismal longevity in the control of the reservoir of neural stem cells. We discovered that Foxo3, a transcription factor that has been implicated in human exceptional longevity, is important for regulating the neural stem cell pool pool. In the past year, we have made extensive progress in characterizing the interaction between Foxo3 and specific chromatin states at target genes in adult neural stem cells, which provides us with a mechanistic view onto how longevity genes can affect specific networks of target genes in neural stem cells in adult organisms. In the past year, we have made significant progress in testing the role of a gene involved in healthspan and longevity in a number of organisms, the deacetylase Sirt1, in adult neural stem cell function. We have observed that Sirt1 inactivation, whether genetic or pharmacological, leads to an increase in oligodendrocyte progenitors, which are cells that are important for myelination of axons. We have found that Sirt1 inactivation is beneficial for models of demyelinating injuries and diseases, which has important consequences for multiple sclerosis. Finally, we are making progress in reprogramming adult human fibroblasts into induced pluripotent stem cells and induced NSCs, with the aim to test the importance of longevity genes in this process.

© 2013 California Institute for Regenerative Medicine