Tissue-resident stem cell activity: a view from the adult Drosophila gastrointestinal tract

Abstract

The gastrointestinal tract serves as a fast-renewing model for unraveling the multifaceted molecular mechanisms underlying remarkably rapid cell renewal, which is exclusively fueled by a small number of long-lived stem cells and their progeny. Stem cell activity is the best-characterized aspect of mucosal homeostasis in mitotically active tissues, and the dysregulation of regenerative capacity is a hallmark of epithelial immune defects. This dysregulation is frequently associated with pathologies ranging from chronic enteritis to malignancies in humans. Application of the adult Drosophila gastrointestinal tract model in current and future studies to analyze the immuno-physiological aspects of epithelial defense strategies, including stem cell behavior and re-epithelialization, will be necessary to improve our general understanding of stem cell participation in epithelial turnover. In this review, which describes exciting observations obtained from the adult Drosophila gastrointestinal tract, we summarize a remarkable series of recent findings in the literature to decipher the molecular mechanisms through which stem cells respond to nonsterile environments.

Keywords: Drosophila; Gastrointestinal tract; Homeostasis; Proliferation and differentiation; Stem cells.

Fig. 1

Atlases of sequential compartments. (Aa) Three discrete domains are defined: the FG, the MG and the HG. (Ab) The MG is divided into the AM, the MM and the PM. (Ac) The AM comprises the AAM and PAM; the PM comprises the APM and PPM. (Ad, Ae) Subdivisions (R0-R5 and A1-P4) are established. (Af) Thirteen subregions ranging from R1a to R5b represent the fine-grained compartmentalization of R0-R5. (B) The close correspondence between R0-R5 and A1-P4. B^R3-R4 indicates the boundary of R3-R4. For example, R2 comprises A2 and A3 (Ba, Ba′), and A2 comprises R2a and R2b (Bb, Bb’)

Fig. 2

Epithelial architecture. a The lineages produced by GsSCs are composed of CCs, ICs and EEs. The LFCs and FCs are present in the posterior CCR. A: anterior, P: posterior. b The MG consists of two types of mature cells, with ISCs that are evenly distributed. c The HPZ is where damage-induced self-renewal is maintained by HSCs. Slow-cycling mode (ASCZ and PSCZ) is maintained by the HSCs in ASCZ. The TA cells in RCZ are involved in the differentiation of DCZ

Fig. 3

Developmental hierarchy. (a) Previous model of ISC division. ISCs and EBs are produced through the mitotic activity of Delta⁺ and esg⁺ ISCs. The EC and EE fates involve Delta/Notch. (b) New model of ISC division. The EE doublets are generated through ISC symmetric division. ISCs also become EEs directly. See text for details. (c) GsSC lineages. High-Notch GBs are committed progenitors for CC and IC differentiation. However, EEs are derived from low-Notch GBs. (d )RNSC lineages. The MTs consist of the SCs, PCs and RCs. These cells are produced by RNSCs through RBs

Fig. 4

Signaling networks for the maintenance of homeostasis. a The factors that control ISC division patterns. (b-d) The signaling pathways that control ISC proliferation and differentiation. Many signaling cascades are crucial for ISC proliferative activity and EC specification. Several signaling cascades are associated with EE differentiation. See text for details. The red dotted lines in all the pictures indicate unknown