Biology subjects

Pin, C.

Publications and source records attributed to Pin, C..

8 recordsLinked to original sources

bioRxiv2025

Intestinal Stem and Progenitor Cells Exhibit Distinct Adaptive Responses to Inflammatory Stress in IBD

BackgroundIntestinal epithelial stem cells (SCs) and their transit-amplifying (TA) progeny are critical for mucosal repair and regeneration. However, their behaviour under chronic inflammatory conditions, such as those observed in Inflammatory Bowel Disease (IBD), remains incompletely understood. MethodsWe investigated the impact of chronic inflammation on intestinal stem/progenitor cells by integrating bulk RNA sequencing from the largest IBD biopsy cohort to date with single-cell transcriptomic analysis and experimental assays using patient-derived intestinal organoids. ResultsActive inflammation was associated with a reduction in canonical LGR5 intestinal stem cells and a concurrent expansion of OLFM4 populations, consistent with an inflammation-induced epithelial repair program. Notably, SC/TA cells from both inflamed and non-inflamed IBD tissues exhibited persistent transcriptional changes that were distinct from those in healthy controls. Single-cell analysis identified transcriptionally heterogeneous SC/TA subpopulations, including a previously uncharacterized inflammation-associated cluster enriched in immune signalling pathways. Pseudotime trajectory analysis demonstrated a shift in differentiation toward deep crypt secretory (Paneth-like) cell lineages under inflammatory conditions. ConclusionsChronic intestinal inflammation reshapes the epithelial stem and progenitor cell compartment, promoting altered differentiation and the emergence of immune-responsive epithelial states. These findings highlight the plasticity of the human intestinal epithelium in IBD and point to new avenues for therapeutic strategies aimed at maintaining epithelial integrity during chronic inflammation.

molecular biology↗

bioRxiv2025

Outer Membrane Vesicles from bacteria expressing the HlyF/CprA family of enzymes are more efficient at delivering their cargo into host cells.

HlyF, a cytoplasmic short-chain dehydrogenase/reductase enzyme encoded by a virulence plasmid in Escherichia coli, and its ortholog CprA, encoded notably by the chromosome of Pseudomonas aeruginosa, drive the production of specific outer membrane vesicles (OMVs). These OMVs have been shown to have the unique abilities to disrupt autophagic flux and exacerbate inflammatory response in host cells. In this study, we demonstrate that these OMVs have improved cargo delivery efficiency through a clathrin-independent internalization pathway into host cells, by directly fusing with the plasma membrane of the host cell. These results reveal an uncovered role of the HlyF/CprA enzyme family in enhancing OMV function through a unique internalization pathway and unveil a novel mechanism driving OMV-mediated virulence.

microbiology↗

bioRxiv2023

Mapping threatened Thai bovids provides opportunities for improved conservation outcomes in Asia

Wild bovids provide important ecosystem functions throughout their ranges. Five wild bovids remain in Thailand: gaur (Bos gaurus), banteng (Bos javanicus), wild water buffalo (Bubalus arnee), mainland serow (Capricornis sumatraensis) and Chinese goral (Naemorhedus griseus). However, their populations and habitats have declined substantially and become fragmented. Here, we identify potentially suitable habitat for these threatened bovids using ecological niche models and quantify how much suitable area remains within protected areas. We combined species occurrence data with environmental variables and used spatially-restricted Biotic-Abiotic-Mobility frameworks with species-specific and single large accessible areas. We used ensembles from eight algorithms for generating maps and out-of-sample predictions to validate model performance against new data. Gaur, banteng, and buffalo models performed well throughout the entire distribution ([≥]62%) and in Thailand ([≥]80%). Mainland serow and Chinese goral performed poorly for the entire distribution and in Thailand, though a 5 km movement buffer markedly improved model performance for serow. Particularly large suitable areas were in Thailand and India for gaur, Cambodia and Thailand for banteng, and India for buffalo. Over 50% of overall suitable habitat is located outside protected areas, with just 9% for buffalo in Thai protected areas, highlighting area for potential habitat management and conflict mitigation.

ecology↗

bioRxiv2022

Homeostasis, injury and recovery dynamics at multiple scales in a self-organizing intestinal crypt

We have built a multi-scale agent-based model (ABM) that reproduces the self-organizing behaviour reported for the intestinal crypt. We demonstrate that a stable spatial organization emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, RNF43/ZNRF3 and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disturbs the cell cycle, cell signalling, proliferation, differentiation and migration and leads to loss of barrier integrity. During recovery, our in-silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug discovery.

systems biology↗

bioRxiv2020

The stress-induced protein NUPR1 orchestrates protein translation during ER-stress by interacting with eIF2-a

NUPR1 is a stress response protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1s well established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely unknown. In this study, we uncover an important role for NUPR1 in participating in the unfolded protein response pathway and the endoplasmic reticulum stress response. Biochemical results, confirmed by ultrastructural morphological observation, revealed alterations in the UPR in acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein translation. Bioinformatical analysis of NUPR1 interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2. Co-immunoprecipitation and proximity ligation assays both confirmed interaction between NUPR1 and eIF2 and its phosphorylated form (p-eIF2). Our. Moreover, our data also suggest loss of NUPR1 in cells results in maintained eIF2 phosphorylation and evaluation of nascent proteins by (peIF2), and click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower post stress protein translational recovery compared to wild-type. Combined, this data proposes a novel role for NUPR1 in the integrated stress response pathway, at least partially through promoting efficient PERK-branch activity and resolution through a unique interaction with eIF2. SignificanceIn the pancreas, NUPR1 is required for a resolution of the ER stress response. During ER stress response, NUPR1 binds both eIF2 allowing for its dephosphorylation and restoration of new protein synthesis. HighlightsBiochemical analysis revealed a general reduction in the protein expression of downstream mediators of the unfolded protein response in the pancreas of mice lacking Nupr1. This finding suggests a novel role for NUPR1 in the UPR/ER stress response. Ultrastructural analysis of pancreata revealed reduced morphological alterations in tunicamycin-treated Nupr1-/- mice compared to Nupr1+/+ mice consistent with a maintained block in general protein translation. Co-immunoprecipitation of tagged NUPR1 confirmed a novel interaction with eIF2. Depletion of NUPR1 prolonged phosphorylation of eIF2, suggesting it may be involved in attenuation of the PERK branch of the UPR. NUPR1-depleted PANC-1 cells displayed a slower recovery of protein translation following UPR activation

cell biology↗

bioRxiv2020

Enteric glia as a source of neural progenitors in adult zebrafish

The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glia markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.

neuroscience↗

bioRxiv2019

RAS mutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis

ABSTRACTChronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with limited treatment options. Whole exome (WES) and targeted sequencing of several independent cohorts of CMML patients, comparing dysplastic (dCMML) to proliferative (pCMML) CMML, as well as paired chronic phase disease and acute leukemic transformation (LT), associate acquisition of oncogenic RAS pathway mutations, the most common being NRASG12D, with aggressive disease and with disease progression. Using patient derived progenitor colony assays and a NRASG12D-Vav-Cre mouse model, we further demonstrate the role of mutant RAS signaling in driving and maintaining pCMML phenotype. RNA-sequencing links RAS pathway mutations with an increased expression of genes encoding the mitotic checkpoint kinases PLK1 and WEE1. Further, we dmeoinstrated that non-mutated lysine methyltransferase KMT2A (MLL1) acts as mediator of NRAS-induced PLK1 and WEE1 expression. Finally, we demonstrate the translational value of our findings by showing that pharmacological PLK1 inhibition decreases monocytosis and hepatosplenomegaly while improving hematopoiesis in RAS mutant patient-derived xenografts. Hence, we define severe CMML as oncogenic RAS pathway-enriched malignancies, with a unique gene expression profile regulated by KMT2A, amenable to therapeutic intervention.

cancer biology↗

bioRxiv2018

Chronic inflammation delays cell migration to villi in the intestinal epithelium

The intestinal epithelium is a single layer of cells which provides the first line of defence of the intestinal mucosa to bacterial infection. Cohesion of this physical barrier is supported by renewal of epithelial stem cells, residing in invaginations called crypts, and by crypt cell migration onto protrusions called villi; dysregulation of such mechanism may render the gut susceptible to chronic inflammation. The impact that excessive or misplaced epithelial cell death may have on villus cell migration is currently unknown. We integrated cell-tracking methods with computational models to determine how epithelial homeostasis is affected by acute and chronic inflammatory cell death. Parameter inference reveals that acute inflammatory cell death has a transient effect on epithelial cell dynamics, whereas cell death caused by chronic inflammation causes a delay in the accumulation of labelled cells onto the villus compared to control. Such a delay may be reproduced by using a cell-based model to simulate the dynamics of each cell in a crypt-villus geometry, showing that a prolonged increase in cell death slows the migration of cells from the crypt to the villus. This investigation highlights which injuries (acute or chronic) may be regenerated and which cause disruption of healthy epithelial homeostasis.

systems biology↗