Tissue stem cells provide for the maintenance and regeneration of organs and tissues throughout life, and the ability of stem cells to contribute to tissue homeostasis depends on their unique ability to generate new stem cells (self-renewal), as well as specialized cell types (differentiation). Stem cells are found in discrete, specialized microenvironments (niches) where they are exposed to diverse systemic and local signals that are integrated with cell intrinsic factors to regulate stem cell behavior. Numerous intrinsic and extrinsic changes occur with age that result in altered stem cell behavior, leading to reduced tissue maintenance and regeneration. This lab has developed Drosophila melanogaster as a system to probe the effects of aging on stem cells and the niche. In the Drosophila testis, stem cells surround and contact the apical hub, a cluster of somatic cells that express the self-renewal factor Unpaired (Upd), which activates the JAK-STAT pathway in adjacent stem cells to specify self-renewal and maintenance. In previous years of this grant, it was shown that aging results in a decrease in upd expression in hub cells. Recent work by the lab has revealed that IGF-II mRNA binding protein (Imp) counteracts endo siRNAs to stabilize upd RNA in hub cells. However, Imp expression decreases in hub cells of older males, similar to upd, which is due to targeting of Imp by the heterochronic microRNA let-7. Therefore, in the absence of Imp, upd mRNA becomes unprotected and susceptible to degradation, leading age-related loss of niche function. Imp and let-7 are also expressed in germ cells, albeit at lower levels, and let-7 is expressed in the midgut of young, but not old, animals. Therefore, this proposal will build upon previous findings by addressing the following Specific Aims:
Specific Aim 1) To characterize the role of Imp in germ cells and germline aging.
Specific Aim 2) To characterize a role for let-7 in the intestinal stem cell niche.
Specific Aim 3) To uncover the mechanism by which let-7 expression changes during aging in the testis and intestine. Reports have indicated that the let-7 family of miRNAs likely target mammalian Imp homologs (Igf2bps1-3). Given the broad role of the let-7 family in aging, stem cells, cancer and metabolism, the regulation of Imp by let-7 is likely an important, conserved mechanism in numerous physiological processes. In addition to providing insights into tissue homeostasis, studies focusing on age-related changes in stem cells and their specialized microenvironments will help to identify and overcome unique hurdles in the manipulation of tissue stem cells derived from older patients and to facilitate the development of techniques for regenerative medicine to treat aging-related diseases.
Stem cell function decreases during the aging process, leading to loss of tissue function. This project seeks to characterize a conserved pathway that contributes to aging of stem cells and the support cells that nurture them. Understanding the mechanistic basis for aging-related changes in stem cell behavior will lead to the development of strategies to treat age-onset diseases and facilitate stem cell based therapies, particularly in older individuals.
|Demarco, Rafael S; Eikenes, Åsmund H; Haglund, Kaisa et al. (2014) Investigating spermatogenesis in Drosophila melanogaster. Methods 68:218-27|
|Voog, Justin; Sandall, Sharsti L; Hime, Gary R et al. (2014) Escargot restricts niche cell to stem cell conversion in the Drosophila testis. Cell Rep 7:722-34|
|Landais, Severine; D'Alterio, Cecilia; Jones, D Leanne (2014) Persistent replicative stress alters polycomb phenotypes and tissue homeostasis in Drosophila melanogaster. Cell Rep 7:859-70|
|Resende, Luis Pedro F; Boyle, Monica; Tran, Darrell et al. (2013) Headcase promotes cell survival and niche maintenance in the Drosophila testis. PLoS One 8:e68026|
|Hur, Jae H; Bahadorani, Sepehr; Graniel, Jacqueline et al. (2013) Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells. Aging (Albany NY) 5:662-81|
|Wong, Chihunt; Jones, D Leanne (2012) Efficiency of spermatogonial dedifferentiation during aging. PLoS One 7:e33635|
|Jones, D Leanne; Rando, Thomas A (2011) Emerging models and paradigms for stem cell ageing. Nat Cell Biol 13:506-12|
|Rera, Michael; Bahadorani, Sepehr; Cho, Jaehyoung et al. (2011) Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab 14:623-34|
|Wang, Lei; Jones, D Leanne (2011) The effects of aging on stem cell behavior in Drosophila. Exp Gerontol 46:340-4|
|Mair, William; McLeod, Catherine J; Wang, Lei et al. (2010) Dietary restriction enhances germline stem cell maintenance. Aging Cell 9:916-8|
Showing the most recent 10 out of 16 publications