Adult stem cells support tissue homeostasis and serve as a cellular reservoir for repair of damaged tissue throughout the life of an individual. However, maintenance and regeneration of tissues such as skin, liver, blood, and muscle decrease dramatically with age. The inability of stem cells to adequately replace aging and damaged tissues is likely a significant contributing factor to age-related decreases in tissue homeostasis and increased incidence of disease. Therefore, it is essential to identify and characterize mechanisms leading to loss of stem cell function, in the context of aging, as strategies to delay or counter loss of stem cell function in older individuals will likely become a important component of regenerative medicine in years to come. Organismal aging is linked to altered metabolism at many levels- from changes in the quantity of extrinsic, systemic factors (ex. hormones, insulin/Insulin-like growth factors) to decreased efficiency of cellular organelles, such as mitochondria. Published data from our lab suggested that enhanced mitochondrial biogenesis in Drosophila melanogaster intestinal stem cells (ISCs) is sufficient to increase lifespan and delay the age-related decline in tissue homeostasis, in both the intestine and male germ line. However, many fundamental questions were raised by these studies. For example, if enhanced mitochondrial biogenesis in stem cells is sufficient to delay tissue aging, what strategies are used by stem cells to maintain a healthy pool of mitochondria? Addressing the links between metabolism, stem cell behavior, tissue homeostasis, and aging is difficult and complex in mammals yet more straightforward in Drosophila, given a relatively short lifespan, conserved signaling pathways that regulate aging and metabolism in mammalian systems, and several discrete populations of adult stem cells. Our preliminary data suggest that maintenance of germline stem cells (GSCs) in the testis of adult Drosophila melanogaster is dependent upon adequate mitochondrial fission and fusion within these cells. Furthermore, we have evidence that GSCs traffic mitochondria to adjacent, post- mitotic, somatic niche cells (hub cells). The frequency of transfer appears to increase with age; therefore, we hypothesize that transfer occurs as one mechanism for GSCs to dispose of damaged mitochondria. Here, I propose to combine cutting-edge electron microscopy (EM) imaging techniques with traditional genetic approaches in Drosophila melanogaster to provide unprecedented insight into the organization, segregation, and structure of mitochondria and mitochondrial proteins in stem cells in intact tissues. In addition to addressing questions regarding mitochondrial transfer, these tools will facilitate analyzing the location and function of many mitochondrial proteins in more detail. Our findings will have major implications for the use of cell-based therapies in the treatment of age-onset and metabolic diseases, particularly in older individuals.
Adult stem cells support tissue homeostasis and serve as a cellular reservoir for repair of damaged tissue throughout the life. This project will combine nove microscopy techniques with traditional genetic approaches to analyze how changes in mitochondria, cellular structures required for energy production, influence stem cell behavior in intact tissues. Understanding how mitochondria influence the ability of stem cells to maintain tissues over time will have major implications for the use of stem cell-based therapies in the course of regenerative medicine, particularly in older individuals and in patients suffering from degenerative, age-onset, and metabolic disorders.
| Koehler, Christopher L; Perkins, Guy A; Ellisman, Mark H et al. (2017) Pink1 and Parkin regulate Drosophila intestinal stem cell proliferation during stress and aging. J Cell Biol 216:2315-2327 |
