Intestinal stem cell response to injury: lessons from Drosophila

Abstract

Many adult tissues and organs are maintained by resident stem cells that are activated in response to injury but the mechanisms that regulate stem cell activity during regeneration are still poorly understood. An emerging system to study such problem is the Drosophila adult midgut. Recent studies have identified both intrinsic factors and extrinsic niche signals that control the proliferation, self-renewal, and lineage differentiation of Drosophila adult intestinal stem cells (ISCs). These findings set up the stage to interrogate how niche signals are regulated and how they are integrated with cell-intrinsic factors to control ISC activity during normal homeostasis and regeneration. Here we review the current understanding of the mechanisms that control ISC self-renewal, proliferation, and lineage differentiation in Drosophila adult midgut with a focus on the niche signaling network that governs ISC activity in response to injury.

Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation

“…Alternatively, other nonapoptotic damage signals produced by infected villus cells may indirectly stimulate WNT secretion from other cell types (e.g., Paneth cells), leading to stem cell activation. Such feedback mechanisms from differentiated cells to stem cells are not well understood in mammalian systems, but several studies in the Drosophila gut have shown the importance of the JAK-STAT pathway (Beebe et al, 2010; Buchon et al, 2009; Jiang et al, 2016; Lin et al, 2010). Stress, injury, and bacterial infection can lead to cytokine production in damaged cells, stimulating the JAK-STAT pathway in WNT-producing cell types, which manifests into ultimate ISC proliferation (Jiang et al, 2016; Xu et al, 2011).…”

“…Such feedback mechanisms from differentiated cells to stem cells are not well understood in mammalian systems, but several studies in the Drosophila gut have shown the importance of the JAK-STAT pathway (Beebe et al, 2010; Buchon et al, 2009; Jiang et al, 2016; Lin et al, 2010). Stress, injury, and bacterial infection can lead to cytokine production in damaged cells, stimulating the JAK-STAT pathway in WNT-producing cell types, which manifests into ultimate ISC proliferation (Jiang et al, 2016; Xu et al, 2011). Our previous study observed a robust upregulation of the interferon pathways in the intestinal epithelium following RV infection in the human intestinal enteroids (Saxena et al, 2017).…”

Gene network underlying the glial regenerative response to central nervous system injury

“…As well as wing disc injury (Díaz‐García and Baonza, ), adult epithelial injury (Rämet et al, ) and embryonic dorsal closure (Noselli and Agnès, ) are also used to investigate wound closure, successfully providing cellular and genetic insights relevant to vertebrates (Juarez, ). The gut is used to study injury responses of intestinal stem cells, regulated by intrinsic signals, and extrinsic niche signals for self‐replication (Jiang et al, ). These findings strongly suggest that regeneration reactivates mechanisms for cell organization normally driving development.…”

Intrinsic regulation of enteroendocrine fate by Numb

“…Notably, local extrinsic feedback signals are critical within the fly intestine to regulate proliferation status of ISCs [reviewed in Jiang et al (2016)]. In theory, the ratio of EE cells within the tissue may be controlled via extrinsic feedback signals, intrinsic regulation, or a combination of both.…”