Age-related stem cell de-regulation by ER stress in the Drosophila intestine. Lifen Wang¹, Hyung Don Ryoo², Heinrich Jasper¹. 1) Buck institute for research on aging.8001 Redwood Blvd, Novato, California. 94945, USA; 2) Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.

   ER stress has been reported to associate with many age-related diseases, such as diabetes, cancer and inflammatory bowel disease, suggesting that loss of protein homeostasis in the ER causes tissue dysfunction in aging animals. The precise cellular basis for this dysfunction, and the impacted regulatory processes, however, remain unclear. Regeneration of the Drosophila intestinal epithelium by Intestinal stem cells (ISC) represents a powerful model system in which to address questions regarding age-related changes in tissue homeostasis. In the aging gut, ISCs become hyperproliferative, resulting in epithelial dysplasia. We have used this model to explore the effects of ER stress and of ER stress response signaling mechanisms on ISC function and on tissue homeostasis. Our results suggest that (I) excessive ER stress causes dysplasia of the intestinal epithelium. (II) Increasing the ability to overcome ER stress by over-expressing XBP1 (which regulates cellular ER stress responses) or Hrd1 (which promotes ER stress associated protein degradation) in ISCs can prevent stress-induced dysplasia. (III) The ER stress response influences ISC proliferation by controlling CncC activity. (IV) Increased ability to alleviate ER stress prevents age-related dysplasia in ISC. It can be anticipated that these studies will provide important new insight into the role of protein homeostasis in the control of stem cell function and the development of age-related stem cell dysfunction.