Secretory Cell Types Research Articles

Placozoan secretory cell types implicated in feeding, innate immunity and regulation of behavior.

Placozoa are millimeter-sized, flat, irregularly shaped ciliated animals that crawl on surfaces in warm oceans feeding on biofilms, which they digest externally. They stand out from other animals due to their simple body plans. They lack organs, body cavities, muscles and a nervous system and have only seven broadly defined morphological cell types, each with a unique distribution. Analyses of single cell transcriptomes of four species of placozoans revealed greater diversity of secretory cell types than evident from morphological studies, but the locations of many of these new cell types were unknown and it was unclear which morphological cell types they represent. Furthermore, there were contradictions between the conclusions of previous studies and the single cell RNAseq studies. To address these issues, we used mRNA probes for genes encoding secretory products expressed in different metacells in Trichoplax adhaerens to localize cells in whole mounts and in dissociated cell cultures, where their morphological features could be visualized and identified. The nature and functions of their secretory granules were further investigated with electron microscopic techniques and by imaging secretion in live animals during feeding episodes. We found that two cell types participate in disintegrating prey, one resembling a lytic cell type in mammals and another combining features of zymogen gland cells and enterocytes. We identified secretory epithelial cells expressing glycoproteins or short peptides implicated in defense. We located seven peptidergic cell types and two types of mucocytes. Our findings reveal mechanisms that placozoans use to feed and protect themselves from pathogens and clues about neuropeptidergic signaling. We compare placozoan secretory cell types with cell types in other animal phyla to gain insight about general evolutionary trends in cell type diversification, as well as pathways leading to the emergence of synapomorphies.

A second wave of Notch signaling diversifies the intestinal secretory lineage.

The small intestine is well known for the function of its nutrient-absorbing enterocytes; yet equally critical for the maintenance of homeostasis is a diverse set of secretory cells, all of which are presumed to differentiate from the same intestinal stem cell. Despite major roles in intestinal function and health, understanding how the full spectrum of secretory cell types arises remains a longstanding challenge, largely due to their comparative rarity. Here, we investigate the fate specification of a rare and distinct population of small intestinal epithelial cells found in rats and humans but not mice: C FTR Hi gh E xpressers (CHEs). We use pseudotime trajectory analysis of single-cell RNA-seq data from rat intestinal jejunum to provide evidence that CHEs are specified along the secretory lineage and appear to employ a second wave of Notch-based signal transduction to distinguish these cells from other secretory cell types. We further validate the general order of transcription factors that direct these cells from unspecified progenitors within the crypt and experimentally demonstrate that Notch signaling is necessary to induce CHE fate both in vivo and in vitro . Our results suggest a model in which Notch is reactivated along the secretory lineage to specify the CHE population: a rare secretory cell type with putative functions in localized coordination of luminal pH and direct relevance to cystic fibrosis pathophysiology.

Protein absorption in the zebrafish gut is regulated by interactions between lysosome rich enterocytes and the microbiome.

Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.

Protein arginine methyltransferase 1 regulates mouse enteroendocrine cell development and homeostasis

BackgroundThe adult intestinal epithelium is a complex, self-renewing tissue composed of specialized cell types with diverse functions. Intestinal stem cells (ISCs) located at the bottom of crypts, where they divide to either self-renew, or move to the transit amplifying zone to divide and differentiate into absorptive and secretory cells as they move along the crypt-villus axis. Enteroendocrine cells (EECs), one type of secretory cells, are the most abundant hormone-producing cells in mammals and involved in the control of energy homeostasis. However, regulation of EEC development and homeostasis is still unclear or controversial. We have previously shown that protein arginine methyltransferase (PRMT) 1, a histone methyltransferase and transcription co-activator, is important for adult intestinal epithelial homeostasis.ResultsTo investigate how PRMT1 affects adult intestinal epithelial homeostasis, we performed RNA-Seq on small intestinal crypts of tamoxifen-induced intestinal epithelium-specific PRMT1 knockout and PRMT1fl/fl adult mice. We found that PRMT1fl/fl and PRMT1-deficient small intestinal crypts exhibited markedly different mRNA profiles. Surprisingly, GO terms and KEGG pathway analyses showed that the topmost significantly enriched pathways among the genes upregulated in PRMT1 knockout crypts were associated with EECs. In particular, genes encoding enteroendocrine-specific hormones and transcription factors were upregulated in PRMT1-deficient small intestine. Moreover, a marked increase in the number of EECs was found in the PRMT1 knockout small intestine. Concomitantly, Neurogenin 3-positive enteroendocrine progenitor cells was also increased in the small intestinal crypts of the knockout mice, accompanied by the upregulation of the expression levels of downstream targets of Neurogenin 3, including Neuod1, Pax4, Insm1, in PRMT1-deficient crypts.ConclusionsOur finding for the first time revealed that the epigenetic enzyme PRMT1 controls mouse enteroendocrine cell development, most likely via inhibition of Neurogenin 3-mediated commitment to EEC lineage. It further suggests a potential role of PRMT1 as a critical transcriptional cofactor in EECs specification and homeostasis to affect metabolism and metabolic diseases.

Intestinal Stem Cells Remodel in Response to Acute Notch Inhibition and Paneth Cell Loss

INTRODUCTION: Intestinal epithelial cells are rapidly renewed throughout life by intestinal stem cells (ISCs). ISC function is regulated by niche factors that orchestrate cellular proliferation and differentiation. Of these, Notch signaling is essential for ISC self-renewal and regulates the cell fate choice between absorptive cells (enterocyte) vs secretory (Paneth, goblet, enteroendocrine, and tuft) cells. Yet, the Notch niche is not fully defined. In the mature small intestine, Paneth cells neighbor each ISC and act as Notch niche cells, providing the Notch signal by expressing the Notch ligands DLL1 and DLL4 on their surface. However, studies in mice have shown that ISCs can function in the immature intestine before Paneth cells are formed, and when Paneth cells are depleted in the adult intestine. We previously observed that acute Notch inhibition via the inhibitor dibenzazepine (DBZ) resulted in Paneth cell apoptosis with intact ISCs displaying transient dysfunction. Here, we aimed to define the Notch niche after Paneth cell apoptosis in adult mice and in the developing intestine. We hypothesized that during acute Notch inhibition, ISCs remodel to compensate for Paneth cell loss by activating Notch ligand expression, and that this remodeling mimics the state of immature ISCs prior to Paneth cell emergence. METHODS: We isolated Lgr5+ ISCs by FACS from Lgr5-GFP-CreERT2 mice 24 hours after DBZ or vehicle treatment and performed bulk RNAseq analysis. To define the Notch niche during development, we analyzed postnatal intestines from Notch ligand reporter mice (Dll1-mCherry and Dll4-mCherry) crossed with the ISC reporter mice (Lgr5-GFP-CreERT2). RESULTS: ISCs isolated from Paneth cell-depleted intestines upregulated expression of Notch ligands Dll4 and Dll4 and various secretory cell markers, with expected downregulation of Notch target genes, but no alteration of other stem cell genes. This suggests that after acute Notch inhibition, Lgr5+ ISCs maintain partial stem cell identity while acquiring a signature resembling that of secretory progenitors. In the immature intestine, we showed by immunohistology that sporadic cells expressing secretory cell markers (LYZ, MUC2, and CHGA) localized to the intervillus region and co-stained with Dll1- or Dll4-mCherry+. This suggests that multiple differentiated cell types could provide the Notch signal to immature ISCs. We also observed occasional Lgr5-GFP+ ISCs that were co-positive for Dll1-mCherry, suggesting that immature ISCs can express Notch ligands at homeostasis. Further experimentation will determine whether these Dll1+ ISCs are similar to the remodeled adult ISCs after Paneth cell depletion. CONCLUSIONS: Acute Notch inhibition directly remodels ISCs to express the Notch ligands, Dll1 and Dll4 in the adult intestine. In the immature intestine, multiple secretory cell types appear to comprise the immature Notch niche. This project was funded by NIH R01 DK118023 awarded to Dr. Linda Samuelson. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cell cycle variants during Drosophila male accessory gland development.

The Drosophila melanogaster male accessory gland (AG) is a functional analog of the mammalian prostate and seminal vesicles containing two secretory epithelial cell types, termed main and secondary cells. This tissue is responsible for making and secreting seminal fluid proteins and other molecules that contribute to successful reproduction. The cells of this tissue are binucleate and polyploid, due to variant cell cycles that include endomitosis and endocycling during metamorphosis. Here, we provide evidence of additional cell cycle variants in this tissue. We show that main cells of the gland are connected by ring canals that form after the penultimate mitosis, and we describe an additional post-eclosion endocycle required for gland maturation that is dependent on juvenile hormone signaling. We present evidence that the main cells of the D. melanogaster AG undergo a unique cell cycle reprogramming throughout organ development that results in step-wise cell cycle truncations culminating in cells containing two octoploid nuclei with under-replicated heterochromatin in the mature gland. We propose this tissue as a model to study developmental and hormonal temporal control of cell cycle variants in terminally differentiating tissues.

PROTEIN ARGININE METHYLTRANSFERASE 1 REGULATES ADULT INTESTINAL CELL PROLIFERATION AND ENTEROENDOCRINE CELLS DIFFERENTIATION

Abstract The adult intestinal epithelium is a complex, self-renewing tissue composed of specialized cell types with diverse functions. Intestinal stem cells (ISCs) at the base of crypts divide and differentiate into absorptive and secretory cells. Enteroendocrine cells (EEC), one type of secretory cells, are the most abundant hormone-producing cells in mammals and involved in the control of energy homeostasis. Many studies investigated the mechanisms that control cell fate determination; however, regulation of EEC development and function are still unclear or controversial. Here, we found that Protein arginine methyltransferase 1(PRMT1), a major arginine methyltransferase, is highly expressed in the proliferating transit-amplifying (TA) cells and ISCs of adult mouse intestinal crypts. By using tamoxifen-induced intestinal epithelial cell-specific deletion of PRMT1 in adult mice, we observed the number of EEC dramatically increased. Transcription analyses showed the expression levels of Enteroendocrine-specific hormone and transcription factors are upregulated in PRMT1-deficient small intestine. In addition, the top enriched upregulated pathways were all associated with EEC functions. Concomitantly, Neurogenin 3-expressing progenitor cells accumulate in the mutant small intestine, and its target genes such as Neuod1, pax4, insm1 are upregulated of mutant crypts by RT-PCR. Furthermore, intestinal epithelium of the mutant mice showed elongated crypts in the small intestine, while increased cell proliferation in TA cells. Additionally, inducible PRMT1 deletion led to increased cell death, which compensated for increased cell proliferation in the crypts to maintain overall intestinal morphology and intestinal homeostasis. Together, our results revealed that the loss of PRMT1 in the adult intestinal epithelium altered TA cell proliferation and EEC differentiation, which was probably via Neurogenin 3-mediated pathway. Thus, our results may provide potential roles of PRMT1 as an essential transcriptional regulator of EECs specification and strategy for metabolic disorder.

Amino acid transporter SLC7A5 regulates cell proliferation and secretary cell differentiation and distribution in the mouse intestine.

The intestine is critical for not only processing nutrients but also protecting the organism from the environment. These functions are mainly carried out by the epithelium, which is constantly being self-renewed. Many genes and pathways can influence intestinal epithelial cell proliferation. Among them is mTORC1, whose activation increases cell proliferation. Here, we report the first intestinal epithelial cell (IEC)-specific knockout (ΔIEC) of an amino acid transporter capable of activating mTORC1. We show that the transporter, SLC7A5, is highly expressed in mouse intestinal crypt and Slc7a5ΔIEC reduces mTORC1 signaling. Surprisingly, adult Slc7a5ΔIEC intestinal crypts have increased cell proliferation but reduced mature Paneth cells. Goblet cells, the other major secretory cell type in the small intestine, are increased in the crypts but reduced in the villi. Analyses with scRNA-seq and electron microscopy have revealed dedifferentiation of Paneth cells in Slc7a5ΔIEC mice, leading to markedly reduced secretory granules with little effect on Paneth cell number. Thus, SLC7A5 likely regulates secretory cell differentiation to affect stem cell niche and indirectly regulate cell proliferation.

Leveraging Temporal Wnt Signal for Efficient Differentiation of Intestinal Stem Cells in an Organoid Model.

The homeostasis of the intestinal epithelium heavily relies on the self-renewal and differentiation of intestinal stem cells (ISCs). Although the orchestration of these processes by signaling pathways such as the Wnt, BMP, Notch, and MAPK signals has been extensively studied, the dynamics of their regulation remains unclear. Our study explores how the Wnt signaling pathway temporally regulates the differentiation of ISCs into various cell types in an intestinal organoid system. We report that the duration of Wnt exposure following Notch pathway inactivation significantly influences the differentiation direction of intestinal epithelial cells toward multiple secretory cell types, including goblet cells, enteroendocrine cells (EECs), and Paneth cells. This temporal regulation of Wnt signaling adds another layer of complexity to the combination of niche signals that govern cell fate. By manipulating this temporal signal, we have developed optimized protocols for the efficient in vitro differentiation of ISCs into EECs and goblet cells. These findings provide critical insights into the dynamic regulation of ISC differentiation and offer a robust platform for future investigations into intestinal biology and potential therapeutic applications.

Infection and inflammation stimulate expansion of a CD74+ Paneth cell subset to regulate disease progression.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

An arrangement of secretory cells involved in the formation and storage of resin in tracheid-based secondary xylem of arborescent plants.

The evolution of the vascular system has led to the formation of conducting and supporting elements and those that are involved in the mechanisms of storage and defense against the influence of biotic and abiotic factors. In the case of the latter, the general evolutionary trend was probably related to a change in their arrangement, i.e. from cells scattered throughout the tissue to cells organized into ducts or cavities. These cells, regardless of whether they occur alone or in a cellular structure, are an important defense element of trees, having the ability to synthesize, among others, natural resins. In the tracheid-based secondary xylem of gymnosperms, the resin ducts, which consist of secretory cells, are of two types: axial, interspersed between the tracheids, and radial, carried in some rays. They are interconnected and form a continuous system. On the other hand, in the tracheid-based secondary xylem of monocotyledons, the resin-producing secretory cells do not form specialized structures. This review summarizes knowledge on the morpho-anatomical features of various types of resin-releasing secretory cells in relation to their: (i) location, (ii) origin, (iii) mechanism of formation, (iv) and ecological significance.

225-LB: Reciprocal Regulatory Interactions of Adipocytes and B Lymphocytes

Obesity, a global health problem, leads to chronic inflammation of adipose tissue (AT), an immune-mediated process linked to metabolic dysfunction and disease, including type II diabetes mellitus. Adipocytes, the most abundant cellular constituent of AT, store lipids and secrete adipokines, a group of hormone-like molecules such as adiponectin and adipsin that regulate metabolism and immune cell functions. In mouse models of diet-induced obesity, distinct subsets of B lymphocytes have been implicated in both exacerbating and mitigating AT inflammation and insulin resistance, but the immunoregulatory mechanisms underlying these effects are incompletely understood. Similarly, whether B lymphocytes and adipocytes engage in regulatory interactions with each other is not known. To investigate this question, we performed in vitro co-culture studies using murine 3T3-L1 adipocytes and I.29µ+ B cells, a murine B cell lymphoma that initiates robust secretion of IgM antibodies and the anti-inflammatory cytokine interleukin (IL)-10 upon activation by lipopolysaccharide (LPS). The induction of IgM and IL-10 secretion was markedly attenuated when I.29µ+ B cells were stimulated with LPS while co-cultured in direct contact with 3T3-L1 adipocytes. This inhibitory effect was also observed, albeit to a lesser degree, when the two cell types were co-cultured but separated by a semipermeable membrane. Conversely, secretion of adiponectin and adipsin by 3T3-L1 adipocytes was reduced when the adipocytes were co-cultured with I.29µ+ B cells, both in direct contact and when separated by a semipermeable membrane. This reduction of adipokine output was observed in both the absence and presence of LPS to activate the B cells. These data support the hypothesis that B lymphocytes and adipocytes can engage in reciprocal interactions that modulate the functions of these two secretory cell types and, in turn, may influence AT homeostasis and inflammation in healthy and obese states. Disclosure J. W. Brewer: None. R. L. Judd: None. M. K. Allman: None. S. R. Carroll: None. S. Granger: None. A. Hall: None. K. Pownall: None. J. Quintana: None. N. Arellano rangel: None. J. Thomas: None. Funding Edward Via College of Osteopathic Medicine Center for One Health

Resolving the origins of secretory products and anthelmintic responses in a human parasitic nematode at single-cell resolution.

Nematode excretory-secretory (ES) products are essential for the establishment and maintenance of infections in mammals and are valued as therapeutic and diagnostic targets. While parasite effector proteins contribute to host immune evasion and anthelmintics have been shown to modulate secretory behaviors, little is known about the cellular origins of ES products or the tissue distributions of drug targets. We leveraged single-cell approaches in the human parasite Brugia malayi to generate an annotated cell expression atlas of microfilariae. We show that prominent antigens are transcriptionally derived from both secretory and non-secretory cell and tissue types, and anthelmintic targets display distinct expression patterns across neuronal, muscular, and other cell types. While the major classes of anthelmintics do not affect the viability of isolated cells at pharmacological concentrations, we observe cell-specific transcriptional shifts in response to ivermectin. Finally, we introduce a microfilariae cell culture model to enable future functional studies of parasitic nematode cells. We expect these methods to be readily adaptable to other parasitic nematode species and stages.

Mechanisms of epithelial growth and development in the zebrafish intestine.

The intestinal epithelium is a complex tissue monolayer composed of regionally and functionally specialized intestinal epithelial cells. Given epithelial exposure to harsh and varied luminal conditions, epithelial cells continuously regenerate to sustain the barrier against environmental factors, including microbial invaders. Multipotent intestinal stem cells are essential to epithelial regenerative capacity, generating a programed mixture of absorptive and secretory cell types. Mechanisms of epithelial growth and differentiation in response to endogenous or external stressors remain under investigation. In this review, we highlight the zebrafish, Danio rerio, as a potent model of intestinal epithelial development and function. We describe epithelial composition and key regulators of epithelial renewal to promote the zebrafish as an investigative tool to study epithelial development and growth. We also highlight areas for discovery, particularly in the context of stress-dependent regulation of epithelial function.

Effect of Intermediate Plus Vaccine and vvIBDV on Bursa Secretory Cells and Their Glycoprotein Production.

There are two types of secretory cells in the chicken bursa of Fabricius (BF): (a) interfollicular epithelial cells (IFE), and (b) bursal secretory dendritic cells (BSDC) in the medulla of bursal follicles. Both cells produce secretory granules, and the cells are highly susceptible to IBDV vaccination and infection. Before and during embryonic follicular bud formation, an electron-dense, scarlet-acid fuchsin positive substance emerges in the bursal lumen, the role of which is unknown. In IFE cells, IBDV infection may induce rapid granular discharge, and in several cells, peculiar granule formation, which suggests that the glycosylation of protein is injured in the Golgi complex. In control birds, the discharged BSDC granules appear in membrane-bound and subsequently solubilized, fine-flocculated forms. The solubilized, fine-flocculated substance is Movat-positive and can be a component of the medullary microenvironment, which prevents the medullary B lymphocytes from nascent apoptosis. Vaccination interferes with the solubilization of the membrane-bound substance, resulting in: (i) aggregation of a secreted substance around the BSDC, and (ii) solid lumps in the depleted medulla. The non-solubilized substance is possibly not "available" for B lymphocytes, resulting in apoptosis and immunosuppression. In IBDV infection, one part of the Movat-positive Mals fuse together to form a medullary, gp-containing "cyst". The other part of Mals migrate into the cortex, recruiting granulocytes and initiating inflammation. During recovery the Movat-positive substance appears as solid, extracellular lumps between the cells of FAE and Mals. Possibly the Mals and Movat-positive extracellular lumps glide into the bursal lumen via FAE to eliminate cell detritus from the medulla.

How do fertile stamens and staminodes go differently in Kingdonia uniflora? Evidence from stamen numbers, ontogeny, and structure

Kingdonia uniflora is in Circaeasteraceae and has fertile stamens and staminodes which are both variable in number; however, the differentiating process of these two types of stamens and the nectariferous structure of staminodes are still unclear. Variation in number and ontogeny (including the degeneration stage of staminodes) of stamens in K. uniflora are investigated under SEM, TEM and LM. The results indicate that there are 63 floral formulas in 80 flowers counted, and the most frequent flower floral formula (4 flowers) is P5A°11A5G6. The correlation between the stamen number and the total floral organ number is high (0.61), while the highest correlation with the total number of floral organs is the number of carpels, and there is a weak correlation between the two types of stamens (-0.23). The stamen development period is divided into five stages, with differentiation of stamens occurring at stage 2. The anther wall formation of fertile stamens is of the basic type, and the simultaneous meiosis form tetrahedral tetrads, while mature pollens are 2-celled and tricolpate. Sporogenous tissue of staminodes fails to develop further at an earlier stage, without the formation of secondary sporogenous cells. The head of mature staminodes has nectary tissue consisting of the secretory epidermis (two types of secretory cells), nectary parenchyma (about 15 layers) and vascular tissue with vessel and sieve tube elements. There are well-developed microchannels in epidermal cell walls, and the cells related to secreting nectar are rich in mitochondria, endoplasmic reticula and small vesicles. In addition, microsporogenesis, male gametophyte development, the secretory function of staminodes, and other characteristics in K. uniflora are similar to those in Ranunculaceae. This study clarifies the differentiating stage of fertile stamens and staminodes and explores the new structure (nectary) that staminodes formed, and also, it enriched the secretion modes in Ranunculales.

A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung

The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.

The Xbp1-regulated transcription factor Mist1 restricts antibody secretion by restraining Blimp1 expression in plasma cells.

Antibody secretion by plasma cells provides acute and long-term protection against pathogens. The high secretion potential of plasma cells depends on the unfolded protein response, which is controlled by the transcription factor Xbp1. Here, we analyzed the Xbp1-dependent gene expression program of plasma cells and identified Bhlha15 (Mist1) as the most strongly activated Xbp1 target gene. As Mist1 plays an important role in other secretory cell types, we analyzed in detail the phenotype of Mist1-deficient plasma cells in Cd23-Cre Bhlha15 fl/fl mice under steady-state condition or upon NP-KLH immunization. Under both conditions, Mist1-deficient plasma cells were 1.4-fold reduced in number and exhibited increased IgM production and antibody secretion compared to control plasma cells. At the molecular level, Mist1 regulated a largely different set of target genes compared with Xbp1. Notably, expression of the Blimp1 protein, which is known to activate immunoglobulin gene expression and to contribute to antibody secretion, was 1.3-fold upregulated in Mist1-deficient plasma cells, which led to a moderate downregulation of most Blimp1-repressed target genes in the absence of Mist1. Importantly, a 2-fold reduction of Blimp1 (Prdm1) expression was sufficient to restore the cell number and antibody expression of plasma cells in Prdm1 Gfp/+ Cd23-Cre Bhlha15 fl/fl mice to the same level seen in control mice. Together, these data indicate that Mist1 restricts antibody secretion by restraining Blimp1 expression, which likely contributes to the viability of plasma cells.

Helminths revive to survive.

Helminth parasites are well known to have co-evolved a diverse arsenal of immunomodulatory factors to aid their persistence following infection. In this issue, Karo-Atar et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20212311) demonstrate that products released by the gut-dwelling helminth Heligmosomoides polygyrus barkeri modify intestinal stem cells into a "revival" state, which is associated with a loss of helminth-expelling secretory cell types from the epithelium.

Single-cell transcriptomics identifies conserved regulators of neuroglandular lineages.

Communication in bilaterian nervous systems is mediated by electrical and secreted signals; however, the evolutionary origin and relation of neurons to other secretory cell types has not been elucidated. Here, we use developmental single-cell RNA sequencing in the cnidarian Nematostella vectensis, representing an early evolutionary lineage with a simple nervous system. Validated by transgenics, we demonstrate that neurons, stinging cells, and gland cells arise from a common multipotent progenitor population. We identify the conserved transcription factor gene SoxC as a key upstream regulator of all neuroglandular lineages and demonstrate that SoxC knockdown eliminates both neuronal and secretory cell types. While in vertebrates and many other bilaterians neurogenesis is largely restricted to early developmental stages, we show that in the sea anemone, differentiation of neuroglandular cells is maintained throughout all life stages, and follows the same molecular trajectories from embryo to adulthood, ensuring lifelong homeostasis of neuroglandular cell lineages.