Juan Flores

Hospital Universitario Virgen Macarena

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Nan Gao

Chinese Academy of Medical Sciences & Peking Union Medical College

Edward M. Bonder

Rutgers, The State University of New Jersey

Michael P. Verzi

Rutgers, The State University of New Jersey

Ronaldo P. Ferraris

Rutgers, The State University of New Jersey

Shiyan Yu

Shanghai Jiao Tong University

Panan Suntornsaratoon

Mahidol University

Eva Alés

Universidad de Sevilla

Iyshwarya Balasubramanian

Rutgers, The State University of New Jersey

Sheila Bandyopadhyay

Rutgers, The State University of New Jersey

Xiaoyang Su

Rutgers, The State University of New Jersey

Cooperative Institutions

Rutgers, The State University of New Jersey

Universidad de Sevilla

Rutgers Sexual and Reproductive Health and Rights

Rutgers New Jersey Medical School

Consejo Superior de Investigaciones Científicas

Rutgers Cancer Institute of New Jersey

Hospital Universitario Virgen del Rocío

Instituto de Biomedicina de Sevilla

Harvard University

Chinese Academy of Sciences

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Rab8a vesicles regulate Wnt ligand delivery and Paneth cell maturation at the intestinal stem cell niche

Development (2015)

Soumyashree Das Shiyan Yu Ryotaro Sakamori Pavan Vedula Qiang Feng

Communication between stem and niche supporting cells maintains the homeostasis of adult tissues. Wnt signaling is a crucial regulator of the stem cell niche, but the mechanism that governs Wnt ligand delivery in this compartment has not been fully investigated. We identified that Wnt secretion is partly dependent on Rab8a-mediated anterograde transport of Gpr177 (wntless), a Wnt-specific transmembrane transporter. Gpr177 binds to Rab8a, depletion of which compromises Gpr177 traffic, thereby weakening the secretion of multiple Wnts. Analyses of generic Wnt/β-catenin targets in Rab8a knockout mouse intestinal crypts indicate reduced signaling activities; maturation of Paneth cells - a Wnt-dependent cell type - is severely affected. Rab8a knockout crypts show an expansion of Lgr5(+) and Hopx(+) cells in vivo. However, in vitro, the knockout enteroids exhibit significantly weakened growth that can be partly restored by exogenous Wnts or Gsk3β inhibitors. Immunogold labeling and surface protein isolation identified decreased plasma membrane localization of Gpr177 in Rab8a knockout Paneth cells and fibroblasts. Upon stimulation by exogenous Wnts, Rab8a-deficient cells show ligand-induced Lrp6 phosphorylation and transcriptional reporter activation. Rab8a thus controls Wnt delivery in producing cells and is crucial for Paneth cell maturation. Our data highlight the profound tissue plasticity that occurs in response to stress induced by depletion of a stem cell niche signal.

Stem cell niche

10.1242/dev.121046

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Citations (50)

Técnica propia: láser endoluminal y cirugía mínimamente invasiva para el tratamiento de la safena interna insuficiente causada por perforante de tipo Hunter incompetente

Revista Mexicana de Angiolog�a (2011)

César Carmelino Juan Flores Reyna Boggiano

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Identification of a New Exo-Endocytic Mechanism Triggered by Corticotropin-Releasing Hormone in Mast Cells

The Journal of Immunology (2015)

Santiago Balseiro-Gómez Juan Flores Jorge Acosta M. Pilar Ramírez-Ponce Eva Alés

Abstract The key role of mast cells (MC), either in development of inflammatory pathologies or in response to environmental stress, has been widely reported in recent years. Previous studies have described the effects of corticotropin-releasing hormone (CRH), which is released from inflamed tissues by cellular stress signals, on MC degranulation, a process possibly driven by selective secretion of mediators (piecemeal degranulation). In this study, we introduce a novel granular exo-endocytic pathway induced by CRH on peritoneal MC. We found that CRH triggers substantial exocytosis, which is even stronger than that induced by Ag stimulation and is characterized by large quantal size release events. Membrane fluorescence increases during stimulation in the presence of FM1-43 dye, corroborating the strength of this exocytosis, given that discrete upward fluorescence steps are often observed and suggesting that secretory granules are preferentially released by compound exocytosis. Additionally, the presence of a depot of large tubular organelles in the cytoplasm suggests that the exocytotic process is tightly coupled to a fast compound endocytosis. This CRH-stimulated mechanism is mediated through activation of adenylate cyclase and an increase of cAMP and intracellular Ca2+, as evidenced by the fact that the effect of CRH is mimicked by forskolin and 8-bromo-cAMP. Thus, these outcomes constitute new evidence for the critical role of MC in pathophysiological conditions within a cellular stress environment and an alternative membrane trafficking route mediated by CRH.

10.4049/jimmunol.1500253

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Citations (11)

Nutrient Cycling and Carbon Burial in the Southern Ocean During the Oligocene and Early Miocene

AGUFM (2002)

Gabriel M. Filippelli Jennifer C. Latimer Sharon L. Kanfoush David A Hodell Katharina Billups

Cycling

Carbon fibers

Nutrient cycle

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Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration

JCI Insight (2020)

Xiao Zhang Sheila Bandyopadhyay Leandro P. Araújo Kevin Tong Juan Flores

The regulatory mechanisms enabling the intestinal epithelium to maintain a high degree of regenerative capacity during mucosal injury remain unclear. Ex vivo survival and clonogenicity of intestinal stem cells (ISCs) strictly required growth response mediated by cell division control 42 (Cdc42) and Cdc42-deficient enteroids to undergo rapid apoptosis. Mechanistically, Cdc42 engaging with EGFR was required for EGF-stimulated, receptor-mediated endocytosis and sufficient to promote MAPK signaling. Proteomics and kinase analysis revealed that a physiologically, but nonconventionally, spliced Cdc42 variant 2 (V2) exhibited stronger MAPK-activating capability. Human CDC42-V2 is transcriptionally elevated in some colon tumor tissues. Accordingly, mice engineered to overexpress Cdc42-V2 in intestinal epithelium showed elevated MAPK signaling, enhanced regeneration, and reduced mucosal damage in response to irradiation. Overproducing Cdc42-V2 specifically in mouse ISCs enhanced intestinal regeneration following injury. Thus, the intrinsic Cdc42-MAPK program is required for intestinal epithelial regeneration, and elevating this signaling cascade is capable of initiating protection from genotoxic injury.

CDC42

Intestinal epithelium

Intestinal mucosa

10.1172/jci.insight.135923

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Citations (22)

The arginine and nitric oxide metabolic pathway regulate the gut colonization and expansion of Ruminococcous gnavus

Journal of Biological Chemistry (2024)

Juan Flores Jayson M. Antonio Panan Suntornsaratoon Vik Meadows Sheila Bandyopadhyay

Metabolic pathway

10.1016/j.jbc.2024.107614

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Rab11 is essential to pancreas morphogenesis, lumen formation and endocrine mass

Developmental Biology (2023)

Haley R. Barlow Neha Ahuja Tyler Bierschenk Yadanar Htike Luke Fassetta

The molecular links between tissue-level morphogenesis and the differentiation of cell lineages in the pancreas remain elusive despite a decade of studies. We previously showed that in pancreas both processes depend on proper lumenogenesis. The Rab GTPase Rab11 is essential for epithelial lumen formation in vitro, however few studies have addressed its functions in vivo and none have tested its requirement in pancreas. Here, we show that Rab11 is critical for proper pancreas development. Co-deletion of the Rab11 isoforms Rab11A and Rab11B in the developing pancreatic epithelium (Rab11pancDKO) results in ∼50% neonatal lethality and surviving adult Rab11pancDKO mice exhibit defective endocrine function. Loss of both Rab11A and Rab11B in the embryonic pancreas results in morphogenetic defects of the epithelium, including defective lumen formation and lumen interconnection. In contrast to wildtype cells, Rab11pancDKO cells initiate the formation of multiple ectopic lumens, resulting in a failure to coordinate a single apical membrane initiation site (AMIS) between groups of cells. This results in an inability to form ducts with continuous lumens. Here, we show that these defects are due to failures in vesicle trafficking, as apical and junctional components remain trapped within Rab11pancDKO cells. Together, these observations suggest that Rab11 directly regulates epithelial lumen formation and morphogenesis. Our report links intracellular trafficking to organ morphogenesis in vivo and presents a novel framework for decoding pancreatic development.

Rab

Lumen (anatomy)

Enteroendocrine cell

10.1016/j.ydbio.2023.05.002

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Citations (6)

Dietary Tryptophan‐Lactobacillus rhamnosus GG Interactions Modify Intestinal Differentiation and Function

The FASEB Journal (2022)

Panan Suntornsaratoon Juan Flores Ravij Upadhyay Paula López Radha Patel

Although the influence of the gut microbiota on structure and proliferation of intestinal epithelial cells has been established, there is disconcordance on information related to cell type differentiation, because most studies on probiotics reflected an outcome from interactions among Lactobacillus, numerous existing microbes, and the host, with limited insight on the specific impact of Lactobacilli spp. For example, L. reuteri enhanced goblet and Paneth cell differentiation in intestine of conventionally-raised chickens with an established commensal gut microbiota, confounding results. Here we fed gnotobiotic mice with tryptophan (t+) or trp-free (t-) diets, followed by monocolonization with LGG (L+, ATCC 53103) or without (control, L-) for a total of 4 groups (L+t+, L+t-, L-t+, L-,t-), then ileum transcriptome was analyzed 3 wk later. L- mice remained germ-free throughout while only LGG was associated with L+. Principal component analysis shows L+ or t+ by itself to modestly cluster away from L-t-, but the cluster depicting the combination of L+t+ was far removed from the others. The heatmap of whole ileum transcriptome shows several distinct groups of genes affected by t+ or by L+ alone. However, the simultaneous impact of L+t+ dramatically upregulates numerous gene clusters while downregulating a few. Volcano plots and Venn diagrams comparing L-t- with L-t+, or L+t- with L-t- indicate ~2300 unique genes affected by L+ (LGG) or t+ (tryptophan) alone. Comparisons between L+t+ and L+t- (effect of t with L) or between L+t+ and L-t+ (effect of L with t) each impact >3800 genes, suggesting that synergistic interactions between L+ and t+ primarily underlie the probiotic impact ascribed to LGG and dietary t. Many of the genes upregulated by L+t+ have functions typical of mature enterocytes: tight junctions, brush border membrane transporters and enzymes, intestinal bile acid metabolism, lipid synthesis and fatty acid b-oxidation. Many downregulated genes are antimicrobial and secreted peptides typical of differentiated Paneth and goblet cells. This latter result was recapitulated when reexamined in conventional mice perfused for 4 h with LGG, as expression of many defensins decreased by >10-fold, suggesting not only that this probiotic's effects can arise from both acute ex vivo and chronic in vivo interactions with the host, but also in hosts housing a complex microbiota. Remarkably, Notch ligands Dll1 and Dll4 typically expressed in Paneth cells as well as Yap1, Axin2 and Ctnnb1 are upregulated in L+t+ ileum, suggesting downstream upregulation of Hes1 and repression of Atoh1, leading to suppression of the secretory lineage. In conclusion, LGG monocolonization may lead to synthesis of t+-derived metabolites by both host and bacteria, leading to an enhancement of absorptive enterocyte functions and suppression of those by goblet and Paneth cells.

Lactobacillus reuteri

Lactobacillus rhamnosus

Mucin 2

10.1096/fasebj.2022.36.s1.r3102

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Proteoglycans involved in bidirectional communication between mast cells and hippocampal neurons

Journal of Neuroinflammation (2019)

Juan Flores María Pilar Ramírez-Ponce María Ángeles Montes Santiago Balseiro-Gómez Jorge Acosta

Mast cells (MCs) in the brain can respond to environmental cues and relay signals to neurons that may directly influence neuronal electrical activity, calcium signaling, and neurotransmission. MCs also express receptors for neurotransmitters and consequently can be activated by them. Here, we developed a coculture model of peritoneal MCs, incubated together with dissociated hippocampal neurons for the study of cellular mechanisms involved in the mast cell-neuron interactions.Calcium imaging was used to simultaneously record changes in intracellular calcium [Ca2+]i in neurons and MCs. To provide insight into the contribution of MCs on neurotransmitter release in rat hippocampal neurons, we used analysis of FM dye release, evoked by a cocktail of mediators from MCs stimulated by heat.Bidirectional communication is set up between MCs and hippocampal neurons. Neuronal depolarization caused intracellular calcium [Ca2+]i oscillations in MCs that produced a quick response in neurons. Furthermore, activation of MCs with antigen or the secretagogue compound 48/80 also resulted in a neuronal [Ca2+]i response. Moreover, local application onto neurons of the MC mediator cocktail elicited Ca2+ transients and a synaptic release associated with FM dye destaining. Neuronal response was partially blocked by D-APV, a N-methyl-D-aspartate receptor (NMDAR) antagonist, and was inhibited when the cocktail was pre-digested with chondroitinase ABC, which induces enzymatic removal of proteoglycans of chondroitin sulfate (CS).MC-hippocampal neuron interaction affects neuronal [Ca2+]i and exocytosis signaling through a NMDAR-dependent mechanism.

Calcium imaging

Premovement neuronal activity

Calcium Signaling

Calcium in biology

10.1186/s12974-019-1504-6

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Citations (6)

Grafts of extra-adrenal chromaffin cells as aggregates show better survival rate and regenerative effects on parkinsonian rats than dispersed cell grafts

Neurobiology of Disease (2007)

Beatriz Galán-Rodríguez Ángel del Marco Juan Flores Susana Ramiro-Fuentes R. González-Aparicio

Nigrostriatal pathway

10.1016/j.nbd.2007.11.009

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Citations (14)