Ditte Skovaa Andersen

In adult tissues, stem cells (SCs) reside in specialized niches, where they remain relatively stationary state until activated by injury. While migration is essential for regeneration, mechanisms guiding SCs towards injury sites remain poorly understood due to challenges in tracking them in vivo. Here, we present an experimental framework to monitor intestinal SC (ISC) movement in real time during early gut regeneration. We identify the Drosophila PDGF-VEGF-related receptor, Pvr, as a critical regulator of this process, with ISC-specific Pvr depletion strongly impairing migration and regeneration. The ligand, Pvf1, produced by gut-associated trachea after damage, serves as a guidance cue directing ISCs towards injury sites. Our work highlights a critical role of gut-trachea crosstalk in guiding ISC migration during regeneration. As neovascularization of injury sites is a key feature of tissue repair in both flies and mammals, these findings could have broader implications for regenerative processes across diverse adult tissues.

Sickness-induced sleep is a behavior conserved across species that promotes recovery from illness, yet the underlying mechanisms are poorly understood. Here, we show that interleukin-6-like cytokine signaling from the Drosophila gut to brain glial cells regulates sleep. Under healthy conditions, this pathway promotes wakefulness. However, elevated gut cytokine signaling in response to oxidative stress – triggered by immune and inflammatory responses in the intestine – induces sleep. The cytokines Unpaired 2 and –3 are upregulated by oxidative stress in enteroendocrine cells and activate JAK–STAT signaling in glial cells, including those of the blood–brain barrier (BBB). This activity maintains elevated sleep during oxidative-stress-induced intestinal disturbances, suggesting that the JAK–STAT pathway in glia inhibits wake-promoting signaling to facilitate sleep-dependent restoration under these conditions. We find that the enteric peptide Allatostatin A (AstA) enhances wakefulness, and during intestinal oxidative stress, gut-derived Unpaired 2/3 inhibits AstA receptor expression in BBB glia, thereby sustaining an elevated sleep state during gut inflammation or illness. Taken together, our work identifies a gut-to-glial communication pathway that couples sleep with intestinal homeostasis and disease, enhancing sleep during intestinal sickness, and contributing to our understanding of how sleep disturbances arise from gastrointestinal disturbances.

Innate immunity serves as a crucial surveillance framework, but can be exploited to facilitate tumor progression. Two new PLOS Biology studies independently show how premalignant cells can exploit Toll-NF-κB signaling, in concert with oncogenic Ras, to enable unchecked growth

In adult tissues, stem cells (SCs) reside in specialized niches, where they are maintained in a quiescent state until activated by injury. Once activated, they migrate towards injured sites, where they proliferate and differentiate to replenish lost or damaged cells. Although effective tissue repair relies critically on the ability of SCs to reach and populate damaged sites, mechanisms guiding SCs towards these sites are not well understood. This is largely due to the technical challenges involved in monitoring SC dynamics in real time in vivo . Here, we devised an experimental framework that allows for real-time tracking of the spatiotemporal dynamics of intestinal SCs (ISCs) during the early phases of gut regeneration. Our data show that ISC migration is rapidly induced following injury and precedes ISC divisions and differentiation. We identify the Drosophila PDGF-VEGF-related receptor, Pvr, as a critical regulator of the migratory response to epithelial damage. ISC-specific Pvr depletion strongly suppresses ISC migration towards affected sites as well as the regenerative response. We further show that the Pvr ligand, PDGF-VEGF-related factor 1 (Pvf1), is produced by the trachea/vasculature in response to intestinal damage and acts as a guidance signal to direct ISC migration towards affected areas. Our work highlights a critical role of gut-trachea/vasculature crosstalk in guiding ISC migration during regeneration. As neovascularization of injured sites is a key feature of tissue repair in both flies and mammals, these findings could be relevant to regenerative processes in a wide range of adult tissues.

While the role of the Tumor necrosis factor-α (referred to as TNF here) as a key mediator of pro-inflammatory and immune responses is well-established, non-pathological functions of the TNF-TNF receptor (TNFR) signaling are less explored. In this issue of The EMBO Journal, Esteban-Collado et al, (2024) describe a TNF independent, pro-survival role of the Drosophila TNFR Wengen during damage-induced tissue regeneration.

Rapidly renewable tissues adapt different strategies to cope with environmental insults. While tissue repair is associated with increased intestinal stem cell (ISC) proliferation and accelerated tissue turnover rates, reduced calorie intake triggers a homeostasis-breaking process causing adaptive resizing of the gut. Here we show that activins are key drivers of both adaptive and regenerative growth. Activin-β (Actβ) is produced by stem and progenitor cells in response to intestinal infections and stimulates ISC proliferation and turnover rates to promote tissue repair. Dawdle (Daw), a divergent Drosophila activin, signals through its receptor, Baboon, in progenitor cells to promote their maturation into enterocytes (ECs). Daw is dynamically regulated during starvation-refeeding cycles, where it couples nutrient intake with progenitor maturation and adaptive resizing of the gut. Our results highlight an activin-dependent mechanism coupling nutrient intake with progenitor-to-EC maturation to promote adaptive resizing of the gut and further establish activins as key regulators of adult tissue plasticity.

Tumor necrosis factor (TNF)-a is a highly conserved proinflammatory cytokine with important functions in immunity, tissue repair, and cellular homeostasis. Due to the simplicity of the Drosophila TNF-TNF receptor (TNFR) system and a broad genetic toolbox, the fly has played a pivotal role in deciphering the mechanisms underlying TNF-mediated physiological and pathological functions. In this review, we summarize the recent advances in our understanding of how local and systemic sources of Egr/TNF contribute to its antitumor and tumor-promoting properties, and its emerging functions in adaptive growth responses, sleep regulation, and adult tissue homeostasis. The recent annotation of TNF as an adipokine and its indisputable contribution to obesity- and cancer-associated metabolic diseases have provoked a new area of research focusing on its dual function in regulating immunity and energy homeostasis. Here, we discuss the role of TNFR signaling in coupling immune and metabolic processes and how this might be relevant in the adaption of host to environmental stresses, or, in the case of obesity, promote metabolic derangements and disease.

It is well established that tumor necrosis factor (TNF) plays an instrumental role in orchestrating the metabolic disorders associated with late stages of cancers. However, it is not clear whether TNF/TNF receptor (TNFR) signaling controls energy homeostasis in healthy individuals. Here, we show that the highly conserved Drosophila TNFR, Wengen (Wgn), is required in the enterocytes (ECs) of the adult gut to restrict lipid catabolism, suppress immune activity, and maintain tissue homeostasis. Wgn limits autophagy-dependent lipolysis by restricting cytoplasmic levels of the TNFR effector, TNFR-associated factor 3 (dTRAF3), while it suppresses immune processes through inhibition of the dTAK1/TAK1-Relish/NF-κB pathway in a dTRAF2-dependent manner. Knocking down dTRAF3 or overexpressing dTRAF2 is sufficient to suppress infection-induced lipid depletion and immune activation, respectively, showing that Wgn/TNFR functions as an intersection between metabolism and immunity allowing pathogen-induced metabolic reprogramming to fuel the energetically costly task of combatting an infection.

Rapidly renewable tissues adapt different strategies to cope with environmental insults. While tissue repair is associated with increased ISC proliferation and accelerated tissue turnover rates, reduced calorie intake triggers a homeostasis-breaking process causing adaptive resizing of the gut. Here we show that activins are key drivers of both adaptive and regenerative growth. Activin-β (Act-β) is produced by progenitor cells in response to intestinal infections and stimulates ISC proliferation and turnover rates to promote tissue repair. Dawdle (Daw), a divergent Drosophila activin, signals through its receptor, Babo ^C , in progenitor cells to promote their maturation into enterocytes (ECs). Daw is dynamically regulated during starvation-refeeding cycles, where it couples nutrient intake with progenitor maturation and adaptive resizing of the gut. Our results highlight an activin-dependent mechanism coupling nutrient intake with progenitor-to-EC maturation to promote adaptive resizing of the gut and further establish activins as key regulators of adult tissue plasticity.

The Drosophila tumour necrosis factor (TNF) ligand-receptor system consists of a unique ligand, Eiger (Egr), and two receptors, Grindelwald (Grnd) and Wengen (Wgn), and therefore provides a simple system for exploring the interplay between ligand and receptors, and the requirement for Grnd and Wgn in TNF/Egr-mediated processes. Here, we report the crystallographic structure of the extracellular domain (ECD) of Grnd in complex with Egr, a high-affinity hetero-hexameric assembly reminiscent of human TNF:TNFR complexes. We show that ectopic expression of Egr results in internalisation of Egr:Grnd complexes in vesicles, a step preceding and strictly required for Egr-induced apoptosis. We further demonstrate that Wgn binds Egr with much reduced affinity and is localised in intracellular vesicles that are distinct from those containing Egr:Grnd complexes. Altogether, our data provide insight into ligand-mediated activation of Grnd and suggest that distinct affinities of TNF ligands for their receptors promote different and non-redundant cellular functions.