Mechanisms of Rejuvenation of Tissue-specific Stem Cells
2004 senior Scholar Award in agingOne of the fundamental aspects of aging that is universal among vertebrates is a change in tissue structure with age. This is evident at the macroscopic and microscopic levels, and is almost invariably accompanied by a decline in the normal functioning of tissues and their ability to respond to injury. It is becoming clear that resident, tissue-specific stem cells serve both to maintain normal homeostasis and to respond to injury or disease by repairing or replacing damage tissue. It is also clear that, with age, there is a decline in functional capacity of these stem cells such that they are less effective as mediators of tissue regeneration. An understanding of the molecular processes that control stem cell survival, proliferative expansion, and commitment to specific lineages is critical to understanding the biology of stem cells and their roles in tissue maintenance. Furthermore, an understanding of the age-related changes in stem cell function is central to explaining how aging impacts tissue structure and function and has the potential to reveal ways to enhance stem cell function in aging tissues.
We have studied tissue-specific stem cells primarily in the context of the biology of skeletal muscle. With age, there is a prominent atrophy of skeletal muscle cells and there is a dramatic decline in the capacity of skeletal muscle to regenerate in response to injury. We have found that muscle stem cells, called ìsatellite cellsî, are critically dependent on the Notch signaling pathway for functional activation. These cells are normally quiescent, but in responses to signals for muscle to grow or regenerate, they activate, begin proliferating, and ultimately progress down a myogenic lineage pathway to form myoblasts which are the key muscle precursor cells. Myoblasts are capable of fusing to existing mature myofibers, which are large multinucleated cells. Myoblasts can also fuse with each other to form new myofibers and replace areas of damaged muscle. If the Notch signaling pathway is inhibited, muscle regeneration is markedly impaired.
We have found that with age, there is a decline in the activation of the Notch signaling pathway in response to injury in skeletal muscle. Therefore, even though the satellite cells are present, they do not receive the appropriate signals and they thus do not repair injured tissue effectively. Most strikingly, we have found that different experimental strategies are able to promote the activation of aged muscle stem cells and to enhance the regeneration of old muscle. If we directly activate the Notch signaling pathway in injured muscle of aged mice, we can significantly enhance the skeletal muscle regeneration. Alternatively, if we expose aged mouse muscle to the systemic milieu of a young mouse by connecting an old mouse to a young mouse parabiotically (in which they develop a shared circulatory system), there is an enhancement of the regenerative properties of the aged muscle. This occurs because the Notch signaling pathway in the old muscle is now activated like it is in young muscle. This effect on enhancing the proliferative responses of tissue-specific stem cells by ìheterochronic parabiosisî is also evident in liver and in brain, where there is an increase in the proliferative activity of resident progenitor cells in those tissues in the old animals.
We are continuing to explore several aspects of this research. First, we are working to understand what the similarities and differences are in the age-related changes in stem cells across different tissues. Second, we are interested to determine that nature of the systemic factors in young animals that have the capacity to enhance tissue-specific stem cell activity. Finally, we are trying to understand how such a signal might work to reprogram the aged stem cells or the environmental niche in which they reside. Ultimately, we hope that our work will contribute to the emerging field of regenerative medicine in which a better understanding of the biology of aging will be translated into healthier aging.