Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

Adult tissue homeostasis requires a tight balance between the removal of old or damaged cells and the production of new ones. Such processes are usually driven by dedicated stem cells that reside within specific tissue locations or niches. The intestinal epithelium has a remarkable regenerative capacity, which has made it a prime paradigm for the study of stem cell-driven tissue self-renewal. The discovery of the presence of stem cells in the adult midgut of the fruit fly Drosophila melanogaster has significantly impacted our understanding of the role of stem cells in intestinal homeostasis. Here we will review the current knowledge of the main mechanisms involved in the regulation of tissue homeostasis in the adult Drosophila midgut, with a focus on the role of stem cells in this process. We will also discuss processes involving acute or chronic disruption of normal intestinal homeostasis such as damage-induced regeneration and ageing

Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult <i>Drosophila</i> midgut

Background: Enteroendocrine cells populate gastrointestinal tissues and are known to translate local cues into systemic responses through the release of hormones into the bloodstream.&lt;p&gt;&lt;/p&gt; Results: Here we report a novel function of enteroendocrine cells acting as local regulators of intestinal stem cell (ISC) proliferation through modulation of the mesenchymal stem cell niche in the &lt;i&gt;Drosophila&lt;/i&gt; midgut. This paracrine signaling acts to constrain ISC proliferation within the epithelial compartment. Mechanistically, midgut enteroendocrine cells secrete the neuroendocrine hormone Bursicon, which acts—beyond its known roles in development—as a paracrine factor on the visceral muscle (VM). Bursicon binding to its receptor, DLGR2, the ortholog of mammalian leucine-rich repeat-containing G protein-coupled receptors (LGR4-6), represses the production of the VM-derived EGF-like growth factor Vein through activation of cAMP.&lt;p&gt;&lt;/p&gt; Conclusions: We therefore identify a novel paradigm in the regulation of ISC quiescence involving the conserved ligand/receptor Bursicon/DLGR2 and a previously unrecognized tissue-intrinsic role of enteroendocrine cells.&lt;p&gt;&lt;/p&gt

Wnt signalling in intestinal stem cells: lessons from mice and flies

Adult stem cells play critical roles in the basal maintenance of tissue integrity, also known as homeostasis, and in tissue regeneration following damage. The highly conserved Wnt signalling pathway is a key regulator of stem cell fate. In the gastrointestinal tract, Wnt signalling activation drives homeostasis and damage-induced repair. Additionally, deregulated Wnt signalling is a common hallmark of age-associated tissue dysfunction and cancer. Studies using mouse and fruit fly models have greatly improved our understanding of the functional contribution of the Wnt signalling pathway in adult intestinal biology. Here, we summarize the latest knowledge acquired from mouse and Drosophila research regarding canonical Wnt signalling and its key functions during stem cell driven intestinal homeostasis, regeneration, ageing and cancer

Intestinal homeostasis and HIV-infection (review)

Постійний баланс між мікробіотою, кишковим бар'єром і мукозною імунною системою є основою нормального кишкового гомеостазу. ВІЛ-інфекція призводить до помітних порушень імунного статусу та структурних пошкоджень слизової оболонки кишечнику, що становить загрозу бар'єрній функції. Ослаблення імунного тиску призводить до дисбіотичних процесів і мікробної транслокації, що викликає хронічну активацію імунної системи і прогресування ВІЛ-інфекції. Хоча впровадження комбінованої антиретровірусної терапії є великим досягненням у лікуванні ВІЛ-інфекції, зберігається потреба у деяких додаткових заходах, спрямованих на відновлення структури та функціональної цілісності кишкового епітелію. Метою огляду є аналіз впливу ВІЛ-інфекції на стан кишкового мікробіоценозу, а також на гіперактивацію імунної системи, асоційованої з розвитком захворювання.Постоянный баланс между микробиотой, кишечным барьером и мукозной иммунной системой является основой нормального кишечного гомеостаза. ВИЧ-инфекция приводит к заметным нарушениям иммунного статуса и структурным повреждениям слизистой оболочки кишечника, что несет угрозу барьерной функции. Ослабление иммунного давления приводит к дисбиотическим процессам и микробной транслокации, что вызывает хроническую активацию иммунной системы и прогрессирование ВИЧ-инфекции. Хотя внедрение комбинированной антиретровирусной терапии является крупным достижением в лечении ВИЧ-инфекции, сохраняется потребность в некоторых дополнительных мерах, направленных на восстановление структуры и функциональной целостности кишечного эпителия. Целью настоящего обзора является анализ влияния ВИЧ- инфекции на состояние кишечной микробиоты, а также на гиперактивацию иммунной системы, ассоциированной с развитием заболеванияPermanent balance between microbiota, intestinal barrier and mucosal immune system is the basis of the normal intestinal homeostasis. HIV infection leads to significant violations of the immune status and structural damage of the intestinal mucosa that is a threat barrier function. The weakening of the immune pressure leads to disbiotic processes and microbial translocation that causes chronic activation of the immune system and the progression of HIV infection. Although the introduction of combined antiretroviral therapy is a great achievement in the treatment of HIV infection remains a need for some additional measures aimed to restore the structure and functional integrity of the intestinal epithelium. The hypothesis that probiotic administration protects the gut surface and can delay progression of HIV infection to the AIDS was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV- 1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria, which upregulate Treg activation, have a promising effect in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections and immune activation contributes to nutritional deficiencies that have lasting consequences. As discussed here, current and emerging studies support the concept that probiotic bacteria can provide specific benefit in HIV-1 infection

c-Src drives intestinal regeneration and transformation

The non‐receptor tyrosine kinase c‐Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult &lt;i&gt;Drosophila&lt;/i&gt; and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage‐induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self‐renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non‐redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation &lt;i&gt;in vivo.&lt;/i&gt

The role of mucosal immunity in the pathogenesis of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of prematurity. Although the precise cause is not well understood, the main risk factors thought to contribute to NEC include prematurity, formula feeding, and bacterial colonization. Recent evidence suggests that NEC develops as a consequence of intestinal hyper-responsiveness to microbial ligands upon bacterial colonization in the preterm infant, initiating a cascade of aberrant signaling events, and a robust pro-inflammatory mucosal immune response. We now have a greater understanding of important mechanisms of disease pathogenesis, such as the role of cytokines, immunoglobulins, and immune cells in NEC. In this review, we will provide an overview of the mucosal immunity of the intestine and the relationship between components of the mucosal immune system involved in the pathogenesis of NEC, while highlighting recent advances in the field that have promise as potential therapeutic targets. First, we will describe the cellular components of the intestinal epithelium and mucosal immune system and their relationship to NEC. We will then discuss the relationship between the gut microbiota and cell signaling that underpins disease pathogenesis. We will conclude our discussion by highlighting notable therapeutic advancements in NEC that target the intestinal mucosal immunity

hnRNP I Inhibits Notch Signaling and Regulates Intestinal Epithelial Homeostasis in the Zebrafish

Regulated intestinal stem cell proliferation and differentiation are required for normal intestinal homeostasis and repair after injury. The Notch signaling pathway plays fundamental roles in the intestinal epithelium. Despite the fact that Notch signaling maintains intestinal stem cells in a proliferative state and promotes absorptive cell differentiation in most species, it remains largely unclear how Notch signaling itself is precisely controlled during intestinal homeostasis. We characterized the intestinal phenotypes of brom bones, a zebrafish mutant carrying a nonsense mutation in hnRNP I. We found that the brom bones mutant displays a number of intestinal defects, including compromised secretory goblet cell differentiation, hyperproliferation, and enhanced apoptosis. These phenotypes are accompanied by a markedly elevated Notch signaling activity in the intestinal epithelium. When overexpressed, hnRNP I destabilizes the Notch intracellular domain (NICD) and inhibits Notch signaling. This activity of hnRNP I is conserved from zebrafish to human. In addition, our biochemistry experiments demonstrate that the effect of hnRNP I on NICD turnover requires the C-terminal portion of the RAM domain of NICD. Our results demonstrate that hnRNP I is an evolutionarily conserved Notch inhibitor and plays an essential role in intestinal homeostasis

Macrobiota — helminths as active participants and partners of the microbiota in host intestinal homeostasis

Important insights have recently been gained in our understanding of the intricate relationship in the intestinal milieu between the vertebrate host mucosal immune response, commensal bacteria, and helminths. Helminths are metazoan worms (macrobiota) and trigger immune responses that include potent regulatory components capable of controlling harmful inflammation, protecting barrier function and mitigating tissue damage. They can secrete a variety of products that directly affect immune regulatory function but they also have the capacity to influence the composition of microbiota, which can also then impact immune function. Conversely, changes in microbiota can affect susceptibility to helminth infection, indicating that crosstalk between these two disparate groups of endobiota can play an essential role in host intestinal immune function and homeostasis