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Waste toner with high carbon content has the potential to become a carbon material, but its utilization is limited due to the low carbonization yield.

Enteroendocrine cells (EECs) in both invertebrates and vertebrates derive from intestinal stem cells (ISCs) and are scattered along the digestive tract, where they function in sensing various environmental stimuli and subsequently secrete neurotransmitters or neuropeptides to regulate diverse biological and physiological processes. To fulfill these functions, EECs are specified into multiple subtypes that occupy specific gut regions. With advances in single-cell technology, organoid culture experimental systems, and CRISPR/Cas9 mediated genomic editing, rapid progress has been made towards characterization of EEC subtypes in mammals. Additionally, studies of genetic model organisms-especially Drosophila melanogaster-have also provided insights about the molecular processes underlying EEC specification from ISCs and about the establishment of diverse EEC subtypes. In this review we compare the regulation of EEC specification and function in mammals and Drosophila, with a focus on EEC subtype characterization, on how internal and external regulators mediate EEC subtype specification, and on how EEC-mediated intra- and inter-organ communications affect gastrointestinal physiology and pathology.

Summary: Intestinal stem cell (ISC) differentiation in the Drosophila midgut requires Delta/Notch-mediated lateral inhibition, which separates the fate of ISCs from differentiating enteroblasts (EBs). Although a canonical Notch signaling cascade is involved in the lateral inhibition, its regulation at the transcriptional level is still unclear. Here we show that the establishment of lateral inhibition between ISC-EB requires two evolutionarily conserved transcriptional co-repressors Groucho (Gro) and C-terminal binding protein (CtBP) that act differently. Gro functions in EBs with E(spl)-C proteins to suppress Delta expression, inhibit cell-cycle re-entry, and promote cell differentiation, whereas CtBP functions specifically in ISCs to mediate transcriptional repression of Su(H) targets and maintain ISC fate. Interestingly, several E(spl)-C genes are also expressed in ISCs that cooperate with Gro to inhibit cell proliferation. Collectively, our study demonstrates separable and cell-type-specific functions of Gro and CtBP in a lateral inhibition process that controls the proliferation and differentiation of tissue stem cells. : In this article, Rongwen Xi and colleagues show that the establishment of lateral inhibition between ISCs and EBs in the Drosophila midgut requires Gro and CtBP that act differently. Gro functions in EBs with E(spl)-C proteins to suppress Delta expression and inhibit cell-cycle re-entry, whereas CtBP functions specifically in ISCs to mediate transcriptional repression of Su(H) targets and maintain ISC fate. Keywords: intestinal stem cell, enteroblast, Groucho, CtBP, Notch, E(spl)-C, lateral inhibition, Drosophila

Summary: Intestinal stem cells (ISCs) are able to generate gut-specific enterocytes, as well as neural-like enteroendocrine cells. It is unclear how the tissue identity of the ISC lineage is regulated to confer cell-lineage fidelity. Here, we show that, in adult Drosophila midgut, loss of the transcriptional repressor Tramtrack in ISCs causes a self-renewal program switch to neural stem cell (NSC)-like, and that switch drives neuroendocrine tumor development. In Tramtrack-depleted ISCs, the ectopically expressed Deadpan acts as a major self-renewal factor for cell propagation, and Sequoia acts as a differentiation factor for the neuroendocrine phenotype. In addition, the expression of Sequoia renders NSC-specific self-renewal genes responsive to Notch in ISCs, thus inverting the differentiation-promoting function of Notch into a self-renewal role as in normal NSCs. These results suggest an active maintenance mechanism for the gut identity of ISCs, whose disruption may lead to an improper acquisition of NSC-like traits and tumorigenesis. : Li et al. show that the loss of a transcriptional repressor, Tramtrack, in adult Drosophila intestinal stem cells causes a self-renewal program switch to neural-stem-cell-like, which drives neuroendocrine tumor development. Keywords: neuroendocrine tumor, NET, neuroblast, tissue identity maintenance factor, TIM factor, reprogramming, cell fate conversion, Dpn, Seq, Suppressor of Hairless

Enteroendocrine cells (EEs) in the intestinal epithelium have important endocrine functions, yet this cell lineage exhibits great local and regional variations that have hampered detailed characterization of EE subtypes. Through single cell RNA-sequencing analysis, combined with a collection of neuropeptide/receptor knock-in strains, here we provide a comprehensive analysis of cellular diversity, spatial distribution and transcription factor (TF) code of EEs in adult Drosophila midgut. We identify 10 major EE subtypes that totally produced 14 different classes of hormone peptides. Each EE on average co-produces 2-5 different classes of hormone peptides. Functional screen with subtype-enriched TFs suggests a combinatorial TF code that controls EE cell diversity, with class-specific TFs Mirr and Ptx1that respectively define two major classes of EEs, and regional TFs such as Esg, Drm, Exex and Fer1that further define regional EE identity. Our single-cell data should greatly facilitate Drosophila modeling of EE differentiation and function.

In adult Drosophila midgut, intestinal stem cells (ISCs) periodically produces progenitor cells that undergo a binary fate choice determined primarily by the levels of Notch activity they receive, before terminally differentiate into enterocytes (ECs) or enteroendocrine cells (EEs). Here we identified Ttk69, a BTB domain-containing transcriptional repressor, as a master repressor of EE cell specification in the ISC lineages. Depletion of ttk69 in progenitor cells induces ISC proliferation and rendered all committed progenitor cells to adopt EE cell specification, leading to the production of supernumerary EE cells in the intestinal epithelium. Conversely, forced expression of Ttk69 in progenitor cells was sufficient to prevent EE cell specification. The expression of Ttk69 was not regulated by Notch signaling, and forced activation of Notch, which is sufficient to induce EC specification of normal progenitor cells, failed to prevent EE cell specification of Ttk69-depleted progenitor cells. We found that loss of Ttk69 led to derepression of acheate-scute complex (AS-C) genes scute and asense, which then induced prospero expression to promote EE cell specification. These studies suggest that Ttk69 functions in parallel with Notch signaling and acts as a master repressor of EE cell specification in Drosophila ISC lineages primarily by suppressing AS-C genes.

Stem cells have a unique ability to self-renewal and a potential to differentiate into one or more types of specialized cells. These properties in vivo are commonly maintained and regulated by signaling pathways involved in cell-to-cell communications. Signaling communications occur between stem cells and the niche supporting cells, as well as between stem cells and their differentiated daughter cells. Different types of stem cells within the same tissue are also coordinately regulated by signaling pathways to maintain tissue architecture and function. Signaling pathways are also critical in mediating stem cell activation in response to tissue damage for accelerated regeneration. This chapter will review signaling mechanisms in controlling various behaviors of several well-characterized tissue stem cells, including self-renewal, differentiation, and regenerative activation of stem cells.

Quiescent, multipotent gastric stem cells (GSSCs) in the copper cell region of adult Drosophila midgut can produce all epithelial cell lineages found in the region, including acid-secreting copper cells, interstitial cells and enteroendocrine cells, but mechanisms controlling their quiescence and the ternary lineage differentiation are unknown. By using cell ablation or damage-induced regeneration assays combined with cell lineage tracing and genetic analysis, here we demonstrate that Delta (Dl)-expressing cells in the copper cell region are the authentic GSSCs that can self-renew and continuously regenerate the gastric epithelium after a sustained damage. Lineage tracing analysis reveals that the committed GSSC daughter with activated Notch will invariably differentiate into either a copper cell or an interstitial cell, but not the enteroendocrine cell lineage, and loss-of-function and gain-of-function studies revealed that Notch signaling is both necessary and sufficient for copper cell/interstitial cell differentiation. We also demonstrate that elevated epidermal growth factor receptor (EGFR) signaling, which is achieved by the activation of ligand Vein from the surrounding muscle cells and ligand Spitz from progenitor cells, mediates the regenerative proliferation of GSSCs following damage. Taken together, we demonstrate that Dl is a specific marker for Drosophila GSSCs, whose cell cycle status is dependent on the levels of EGFR signaling activity, and the Notch signaling has a central role in controlling cell lineage differentiation from GSSCs by separating copper/interstitial cell lineage from enteroendocrine cell lineage.