103 Oral - Stem Cells, Regeneration, and Tissue Repair
Friday April 08, 12:15 PM - 12:30 PM

Re-entry into mitosis and regeneration of intestinal stem cells through enteroblast dedifferentiation in Drosophila midguts


Authors:
Aiguo Tian 1; Virginia Morejon 1; Sarah Kohoutek 1; Yi-Chun Huang 1; Wu-Min Deng 1; Jin Jiang 2

Affiliations:
1) Tulane University; 2) UT Southwestern Medical Center

Keywords:
d. intestinal stem cells; x. homeostasis

Colorectal cancer (CRC) is the 3rd most common cancer diagnosed in the United States. Intestinal dysplasia is considered as a precursor lesion of CRC in mammals and can be mimicked in Drosophila. Dysplasia is characterized by hyperproliferation and accumulation of intestinal stem cells (ISCs) and enteroblasts (EBs). As a result of dysplasia, the lifespan is shortened. Current studies in Drosophila indicate that only resident ISCs can divide and their over-proliferation results in intestinal dysplasia. In addition, enteroblasts (EBs) as one type of ISC progenies are accumulated under intestinal dysplasia. Thus, our studies use the Drosophila intestine as a model to understand how EBs contribute to dysplasia in response to infection of pathogenic bacteria. Here we find that infection of pathogenic bacteria induces enteroblasts (EBs) as one type of ISC progenies to re-enter the mitotic cycle in the Drosophila intestine. The re-entry into mitosis is dependent on epithermal growth factor receptor (EGFR)-Ras signaling and ectopic activation of EGFR-Ras signaling in EBs is sufficient to drive EBs cell-autonomously to re-enter into mitosis. In addition, we examined whether EBs gain ISC identity as a prerequisite to divide, but the immunostaining with stem cell marker Delta shows that these dividing EBs do not gain ISC identity. After employing lineage tracing experiments, we further demonstrate that EBs dedifferentiate to generate functional ISCs after symmetric divisions of EBs. Together, our study in Drosophila intestines uncovers a new role of EGFR-Ras signaling in regulating re-entry into mitosis and dedifferentiation during regeneration and reveals a novel mechanism by which ISC progenies undergo dedifferentiation through a mitotic division, which has important implication to increase of ISC pool and intestinal dysplasia.