Tracing oncogene-driven remodelling of the intestinal stem cell niche.

Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1-3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model-the Red2Onco system-that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFRloCD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.Royal Societ

Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor

Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups

Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells.

The gastric corpus epithelium is the thickest part of the gastrointestinal tract and is rapidly turned over. Several markers have been proposed for gastric corpus stem cells in both isthmus and base regions. However, the identity of isthmus stem cells (IsthSCs) and the interaction between distinct stem cell populations is still under debate. Here, based on unbiased genetic labeling and biophysical modeling, we show that corpus glands are compartmentalized into two independent zones, with slow-cycling stem cells maintaining the base and actively cycling stem cells maintaining the pit-isthmus-neck region through a process of "punctuated" neutral drift dynamics. Independent lineage tracing based on Stmn1 and Ki67 expression confirmed that rapidly cycling IsthSCs maintain the pit-isthmus-neck region. Finally, single-cell RNA sequencing (RNA-seq) analysis is used to define the molecular identity and lineage relationship of a single, cycling, IsthSC population. These observations define the identity and functional behavior of IsthSCs.Wellcome Trust Royal Societ

A Key Role for Neurotensin in Chronic-Stress-Induced Anxiety-Like Behavior in Rats

Accepted ManuscriptChronic stress is a major cause of anxiety disorders that can be reliably modeled preclinically, providing insight into alternative therapeutic targets for this mental health illness. Neuropeptides have been targeted in the past to no avail possibly due to our lack of understanding of their role in pathological models. In this study we use a rat model of chronic stress-induced anxiety-like behaviors and hypothesized that neuropeptidergic modulation of synaptic transmission would be altered in the bed nucleus of the stria terminalis (BNST), a brain region suspected to contribute to anxiety disorders. We use brain slice neurophysiology and behavioral pharmacology to compare the role of locally released endogenous neuropeptides on synaptic transmission in the oval (ov) BNST of non-stressed (NS) or chronic unpredictably stressed (CUS) rats. We found that in NS rats, post-synaptic depolarization induced the release of vesicular neurotensin (NT) and corticotropin-releasing factor (CRF) that co-acted to increase ovBNST inhibitory synaptic transmission in 59% of recorded neurons. CUS bolstered this potentiation (100% of recorded neurons) through an enhanced contribution of NT over CRF. In contrast, locally released opioid neuropeptides decreased ovBNST excitatory synaptic transmission in all recorded neurons, regardless of stress. Consistent with CUS-induced enhanced modulatory effects of NT, blockade of ovBNST NT receptors completely abolished stress-induced anxiety-like behaviors in the elevated plus maze paradigm. The role of NT has been largely unexplored in stress and our findings highlight its potential contribution to an important behavioral consequence of chronic stress, that is, exaggerated avoidance of open space in rats.CPN was funded by CIHR Vanier Graduate Scholarship (338319); APVS was funded by Fundação para a Ciência e Tecnologia (SFRH/BPD/52078/2013); ERH was funded by CIHR Postdoctoral Fellowship (MFE-123712); SA was funded by a Queen Elizabeth II Graduate Scholarship in Science and Technology; ÉCD was funded by the Canadian Institute of Health Research (MOP-25953)info:eu-repo/semantics/publishedVersio

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder

Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci.We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan.Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system.Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients.Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD

Stem and Progenitor Cells in Homeostatic Maintenance and Perturbation of the Pulmonary Epithelium

The histological changes which occur in the step-wise progression from a normal pseudostratified airway epithelium to lung squamous cell carcinoma in situ are well documented. However, the contribution of mutated tissue stem or progenitor cells to this process are poorly understood at the level of clonal resolution. Secretory cells are known progenitor cells of the pseudostratified airway epithelium, however their clonal dynamics in homeostasis are unknown. Here, I elucidate their contribution to homeostasis, and reveal they are more persistent in the epithelium than previously predicted. Single mutations cannot consistently give rise to lung squamous cell carcinoma, however why this is the case is not known. Hyperactivation of the PI3K pathway is one of the earliest events in lung squamous cell carcinoma development. As such, I generate a novel lineage tracing mouse line, Red2-PIK3CAH1047R, which allows for the simultaneous lineage tracing of PIK3CAH1047R mutant cells and tissue-sharing wild-type cells. I then initiate recombination of the reporter in a starting population of basal cells, the known stem cell of the pseudostratified airway epithelium, or secretory cells, known progenitors. I reveal that in both lineage traces, PIK3CAH1047R mutant cells can differentiate into typical lineage trajectories, although they do form larger clones than tissue sharing counterparts. Conversely, the clonal dynamics of wild-type tissue-sharing counterparts do not alter from homeostatic behaviour. These findings were confirmed with single cell RNA sequencing, which also indicates reduced signalling between SecC-derived PIK3CAH1047R mutant cells and tissue-sharing basal cells. I also performed a detailed analysis examining the ability of intralobar secretory cells with constitutive Notch signalling to contribute to the alveolar lineages after injury. Bronchiolisation of the alveoli is observed in human diseases which impair alveolar function, such as idiopathic pulmonary fibrosis. I show that constitutive Notch signalling in intralobar secretory cells allows them to leave their airway compartment, enter the alveolar region, but fail to properly differentiate. Therefore, in my doctoral studies, I make a novel contribution to the field, including: (1) defining the clonal dynamics of secretory cells in the pseudostratified airway epithelium, (2) generating and validating a novel lineage tracing mouse line, Red2-PIK3CAH1047R, (3) defining the changes induced by PIK3CAH1047R mutation in basal cells and secretory cells of the pseudostratified airway epithelium, and (4) defining the effect of constitutive Notch signalling abrogating the capacity of intralobar secretory cells to repair the alveolar epithelium

Open Innovation in European industries ::executive summary

The European Academic Network for Open Innovation – (OI-Net) is an EU co-financed project designed to promote coopera,on on open innovation research and educa,on. It consists of 51 academic and industrial partners from 35 European countries. One of the outcomes of this project is the first European Survey on IdenCficaCon of Industrial Needs for Open InnovaCon EducaCon. The OI-Net project partners collected over 500 responses from European companies (large, SMEs, and micro firms) and this execu,ve report provides the summary of the key findings on the adop,on of open innova,on in companies, self-perceived status of open innova,on and importance of skills and abili,es that open innova,on specialist should possess. Also this report presents comparison of the open innova,on ac,vi,es between companies who claim to adopt open innova,on (adopters), plan to adopt (planners) and those who do not adopt and not planning to adopt it in the future (non adopters)

The Influence of Sea Ice Cover and Atlantic Water Advection on Annual Particle Export North of Svalbard

The Arctic Ocean north of Svalbard has recently experienced large sea ice losses and the increasing prominence of Atlantic water (AW) advection. To investigate the impact of these ongoing changes on annual particle export, two moorings with sequential sediment traps were deployed in ice-free and seasonally ice-covered waters on the shelf north (NSv) and east (ESv) of Svalbard, collecting sinking particles nearly continuously from October 2017 to October 2018. Vertical export of particulate organic carbon (POC), total particulate matter (TPM), planktonic protists, chlorophyll a, and zooplankton fecal pellets were measured, and swimmers were quantified and identified. Combined with sensor data from the moorings, these time-series measurements provided a first assessment of the factors influencing particle export in this region of the Arctic Ocean. Higher annual TPM and POC fluxes at the ice-free NSv site were primarily driven by the advection of AW, higher grazing by large copepods, and a wind-induced mixing event during winter. Higher diatom fluxes were observed during spring in the presence of sea ice at the ESv site. Along with sea ice cover, regional differences in AW advection and the seasonal presence of grazers played a prominent role in the biological carbon pump along the continental shelf off Svalbard

Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration

AbstractWhile the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying molecular mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Upon damage, IL-1β signalling-dependent modulation of Jag1/2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives reprogramming and acquisition of differentiation plasticity. We identify a core role for the transcription factor Fosl2/Fra2 in secretory cell fate conversion to alveolar type 2 (AT2) cells retaining the distinct genetic and epigenetic signatures of secretory lineages. We furthermore reveal that KDR/FLK-1+ human secretory cells display a conserved capacity to generate AT2 cells via Notch inhibition. Our results demonstrate the functional role of a IL-1β-Notch-Fosl2 axis for the fate decision of secretory cells during injury repair, proposing a new potential therapeutic target for human lung alveolar regeneration.</jats:p