The human gut has the largest surface area (400 m2) among all organs, whose size and shape are actively controlled and maintained. The gastrointestinal tract poses severe clinical problems upon chronic injury as in inflammatory bowel disease (ulcerative colitis and Crohn´s disease) during chemotherapy or targeted therapy. At least seven unique differentiated cell types are known to form the gut and they originate from intestinal epithelial stem cells (IESC). Homeostasis refers to the process maintaining the size of an organ through controlling the overall number of cells. The production of new cells by stem cells needs to be in balance with loss of cells, due to damage or injury. When a tissue is injured the homeostatic response by IESCs is enhanced to repair damaged tissue. Proper regeneration to its original state and size needs tight control, since too much stem cell proliferation contributes to cancer onset. The transcription factor STAT5 mediates intestinal cytokine and growth factor signals that were shown to control intestinal inflammation upon injury. However, the underlying mechanisms have remained unclear until recently.
The Image shows sections through the wall of the gut of mice with normal (left), excessive or reduced (right) STAT5 expression. The brown stain identifies cells which have undergone cell division and the increased level in the middle panel indicates a higher proliferation level of the tissue with excessiove STAT5 activation, while reduced STAT5 decreases proliferation compared to control tissue.
Xiaonan Han, Richard Moriggl and their team of researchers from the Cincinnati Children´s Hospital in collaboration with several groups from the University of Veterinary Medicine, the Medical University Vienna and the Ludwig Boltzmann Institute for Cancer Research, now link STAT5 signalling to IESC replenishment upon injury. Using genetic model systems, the international consortium associates depletion of Stat5 gene to decreased proliferation of a specific subset of IESC pools. Mice lacking STAT5 were more prone to gastrointestinal injury upon colitis, infectious disease or gamma-irradiation challenge. Inducible expression of STAT5 increased IESC proliferation, accelerated crypt regeneration, and conferred resistance to intestinal injury. Furthermore, ectopic activation of STAT5 in mouse or human stem cells promoted self-renewal. Therefore STAT5 is a functional therapeutic target to improve the IESC regenerative response to gut injury.
These findings were recently published in the prestigious journal “stem cell reports” under the title "www.sciencedirect.com/science/article/pii/S2213671114003816">http://www.sciencedirect.com/science/article/pii/S2213671114003816">Activated STAT5 Confers Resistance to Intestinal Injury by Increasing Intestinal Stem Cell Proliferation and Regeneration"