Inhibition of BMP2 and BMP4 Represses Barrett’s Esophagus While Enhancing the Regeneration of Squamous Epithelium in Preclinical Models

European Research Council (ERC) starting grant: ERC-StG 282079 TargetS4BarretERC-POC 632258 BMP4EACDutch government grant: LSH-TKI-PPP 2017Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, ISCIII-Subdirección General de Evaluación y Fomento de la InvestigaciónMinisterio de Economía y Competitividad, Spain (grant PI16/01642 & PI10/01096

Decidualization modulates the mesenchymal stromal/stem cell and pericyte characteristics of human decidual stromal cells. Effects on antigen expression, chemotactic activity on monocytes and antitumoral activity

Decidual stromal cells (DSCs) are the most abundant cellular component of human decidua and play a central role in maternal–fetal immune tolerance. Antigen phenotyping and functional studies recently confirmed the relationship of DSCs with mesenchymal stem/stromal cells (MSCs) and pericytes, the latter two cell types being closely related or identical. The present study investigated the effect of decidualization, a process of cell differentiation driven by progesterone (P4) and other pregnancy hormones, on the MSC/pericyte characteristics of DSCs. To this end we isolated undifferentiated DSC (preDSC) lines that were decidualized in vitro (dDSC) by the effect of P4 and cAMP. Using flow cytometry, we found significant downmodulation of the expression of the MSC/pericyte markers α-smooth muscle actin, nestin, CD140b, CD146 and SUSD2 in dDSCs. The dDSCs did not differ, compared to preDSCs, in the expression of angiogenic factors (characteristic of pericytes) HGF, FGF2, ANGPT1 or VEGF according to RT-PCR results, but had significantly increased PGF expression. In migration assays, preDSC-conditioned media had a chemotactic effect on the THP-1 monocytic line (characteristic of pericytes), and this effect was significantly greater in dDSCconditioned media. Media conditioned with dDSC, but not with preDSC, induced apoptosis in 4 out of 6 different tumor cell lines (characteristic of MSCs) according to propidium iodide staining and flow cytometry results. Our findings show that decidualization induces phenotypic and functional changes in the MSC/pericyte properties of DSCs that may have a role in the normal development of pregnancy.This article contributes to COST Action CA17116 “International Network for Translating Research on Perinatal Derivatives into Therapeutic Approaches (SPRINT)”, supported by COST (European Cooperation in Science and Technology)

Brote nosocomial de COVID-19 en una planta de medicina interna: probable transmisión aérea

Transmissió aèria; Brot; COVID-19Transmisión aérea; Brote; COVID-19Airborne transmission; Outbreak; COVID-19Background and objectives: Despite the increasing evidence supporting the importance of airborne transmission in SARS-CoV-2 infection, it has not been considered relevant in the vast majority of reported nosocomial outbreaks of COVID-19. The aim of this study is to describe a nosocomial outbreak of SARS-CoV-2 infection whose features suggest that aerosol transmission had an important role. Methods: This is a descriptive analysis of a nosocomial outbreak of SARS-CoV-2 infection in an internal medicine ward that occurred in December 2020. All cases were confirmed by a positive PCR test for SARS-CoV-2. Results: From December 5 to December 17, 21 patients and 44 healthcare workers (HCWs) developed a nosocomial SARS-CoV-2 infection. Fifty-one of the 65 cases (78.5%) were diagnosed between December 6 and 9. The attack rate in patients was 80.8%. Among HCWs, the attack rate was higher in those who had worked at least one full working day in the ward (56.3%) than in those who had occasionally been in the ward (25.8%; p = 0.005). Three days before the first positive case was detected, two extractor fans were found to be defective, affecting the ventilation of three rooms. Sixteen cases were asymptomatic, 48 cases had non-severe symptoms, and 2 cases required admission to the intensive care unit. All patients eventually recovered. Conclusion: The high attack rate, the explosive nature of the outbreak, and the coincidence in time with the breakdown in air extractors in some rooms of the ward suggest that airborne transmission played a key role in the development of the outbreak.Antecedentes y objetivos A pesar de los datos cada vez mayores que respaldan la importancia de la transmisión aérea en la infección por el SARS-CoV-2, en la inmensa mayoría de los brotes nosocomiales descritos de COVID-19 no se ha considerado relevante. El objetivo de este estudio consiste en describir un brote nosocomial de infección por el SARS-CoV-2 cuyas características indican que la transmisión por aerosoles desempeñó un papel importante. Métodos Se trata de un análisis descriptivo de un brote nosocomial de infección por el SARS-CoV-2 en una planta de Medicina Interna que tuvo lugar en diciembre de 2020. Todos los casos se confirmaron mediante una PCR positiva para SARS-CoV-2. Resultados Entre el 5 y el 17 de diciembre, 21 pacientes y 44 profesionales sanitarios contrajeron una infección nosocomial por el SARS-CoV-2. De los 65 casos, 51 (78,5%) se diagnosticaron entre el 6 y el 9 de diciembre. La tasa de ataque en los pacientes fue del 80,8%. Entre los profesionales sanitarios, la tasa de ataque fue mayor en los que habían trabajado al menos una jornada laboral completa en la planta (56,3%) que en los que habían estado ocasionalmente en ella (25,8%; p = 0,005). Tres días antes de detectar el primer caso positivo se identificó una avería en dos extractores de aire, que afectó a la ventilación de tres habitaciones. Dieciséis casos cursaron de forma asintomática, 48 manifestaron síntomas leves y 2 precisaron ingreso en la unidad de cuidados intensivos. Todos los casos se recuperaron finalmente. Conclusiones La elevada tasa de ataque, la naturaleza explosiva del brote y la coincidencia en el tiempo con la avería de los extractores de aire en algunas habitaciones de la planta indican que la transmisión aérea desempeñó un papel fundamental en el desarrollo del brote

Influence of the ectopic location on the antigen expression and functional characteristics of endometrioma stromal cells

Research question: Are the alterations observed in the endometriotic cells, such as progesterone resistance, already present in the eutopic endometrium or acquired in the ectopic location? Design: The response to decidualization with progesterone and cyclic AMP for up to 28 days was compared in different endometrial stromal cell (EnSC) lines established from samples of endometriomas (eEnSC), eutopic endometrium from women with endometriosis (eBEnSC), endometrial tissue from healthy women (BEnSC) and menstrual blood from healthy donors (mEnSC). Results: Usual features of decidualized cells, such as changes in cell morphology and expression of prolactin, were similarly observed in the three types of eutopic EnSC studied, but not in the ectopic cells upon decidualization. Among the phenotypic markers analysed, CD105 was down-regulated under decidualization in all cell types (mEnSC, P = 0.005; BEnSC, P = 0.029; eBEnSC, P = 0.022) except eEnSC. mEnSC and BEnSC underwent apoptosis during decidualization, whereas eBEnSC and eEnSC were resistant to the induction of cell death. Lastly, migration studies revealed that mEnSC secreted undetermined factors during decidualization that inhibited cell motility, whereas eEnSC showed a significantly lower ability to produce those migration-regulating factors (P < 0.0001, P  < 0.001 and P = 0.0013 for the migration of mEnSC at 24, 48 and 72 h, respectively; P  < 0.0001 for the migration of eEnSC at all times studied). Conclusions: This study provides novel insights into the differences between endometriotic and eutopic endometrial cells and reinforces the idea that the microenvironment in the ectopic location plays additional roles in the acquisition of the alterations that characterize the cells of the endometriotic foci.This work was supported by the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016, ISCIII Subdirección General de Evaluación y Fomento de la Investigación, Ministerio de Economía y Competitividad, Spain (Grant PI16/01642); the European Regional Development Fund (ERDF/634 FEDER funding); and the Plan Propio, Universidad de Granada (Grant PP2021.PP-12)

Inhibitor of apoptosis proteins, NAIP, cIAP1 and cIAP2 expression during macrophage differentiation and M1/M2 polarization

Monocytes and macrophages constitute the first line of defense of the immune system against external pathogens. Macrophages have a highly plastic phenotype depending on environmental conditions; the extremes of this phenotypic spectrum are a pro-inflammatory defensive role (M1 phenotype) and an anti-inflammatory tissue-repair one (M2 phenotype). The Inhibitor of Apoptosis (IAP) proteins have important roles in the regulation of several cellular processes, including innate and adaptive immunity. In this study we have analyzed the differential expression of the IAPs, NAIP, cIAP1 and cIAP2, during macrophage differentiation and polarization into M1 or M2. In polarized THP-1 cells and primary human macrophages, NAIP is abundantly expressed in M2 macrophages, while cIAP1 and cIAP2 show an inverse pattern of expression in polarized macrophages, with elevated expression levels of cIAP1 in M2 and cIAP2 preferentially expressed in M1. Interestingly, treatment with the IAP antagonist SMC-LCL161, induced the upregulation of NAIP in M2, the downregulation of cIAP1 in M1 and M2 and an induction of cIAP2 in M1 macrophages.This work was supported by Universidad de Granada, Plan Propio 2015;#P3B: FAM, VMC (http://investigacion.ugr.es/pages/planpropio/2015/ resoluciones/p3b_def_28072015); Universidad de Granada CEI BioTic;#CAEP2-84: VMC (http:// biotic.ugr.es/pages/resolucionprovisional enseaanzapractica22demayo/!); and Canadian nstitutes of Health Research;#231421, #318176, #361847: STB, ECL, RK (http://www.cihr-irsc.gc. ca/e/193.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Cutting edge: Slamf8 is a negative regulator of Nox2 activity in macrophages

Slamf8 (CD353) is a cell surface receptor that is expressed upon activation of macrophages (MΦs) by IFN-γ or bacteria. In this article, we report that a very high NADPH oxidase (Nox2) enzyme activity was found in Slamf8 -/- MΦs in response to Escherichia coli or Staphylococcus aureus, as well as to PMA. The elevated Nox2 activity in Slamf8 -/- MΦs was also demonstrated in E. coli or S. aureus phagosomes by using a pH indicator system and was further confirmed by a reduction in the enzyme activity after transfection of the receptor into Slamf8-deficient primary MΦs or RAW 264.7 cells. Upon exposure to bacteria or PMA, protein kinase C activity in Slamf8 -/- MΦs is increased. This results in an enhanced phosphorylation of p40phox, one key component of the Nox2 enzyme complex, which, in turn, leads to greater Nox2 activity. Taken together, the data show that, in response to inflammation-associated stimuli, the inducible receptor Slamf8 negatively regulates inflammatory responses. Copyright © 2012 by The American Association of Immunologists, Inc.NIH (AI-15066); Ministry of Education and Science of Spain (SAF2006-08529; SAF2007-62562); Crohn’s and Colitis Foundation of AmericaPeer Reviewe

Menstrual blood-derived stromal cells modulate functional properties of mouse and human macrophages.

Menstrual blood-derived stromal cells (MenSCs) are emerging as a strong candidate for cell-based therapies due to their immunomodulatory properties. However, their direct impact on innate immune populations remains elusive. Since macrophages play a key role in the onset and development of inflammation, understanding MenSCs implication in the functional properties of these cells is required to refine their clinical effects during the treatment of inflammatory disorders. In this study, we assessed the effects that MenSCs had on the recruitment of macrophages and other innate immune cells in two mouse models of acute inflammation, a thioglycollate (TGC)-elicited peritonitis model and a monobacterial sepsis model. We found that, in the TGC model, MenSCs injection reduced the percentage of macrophages recruited to the peritoneum and promoted the generation of peritoneal immune cell aggregates. In the sepsis model, MenSCs exacerbated infection by diminishing the recruitment of macrophages and neutrophils to the site of infection and inducing defective bacterial clearance. Additional in vitro studies confirmed that co-culture with MenSCs impaired macrophage bactericidal properties, affecting bacterial killing and the production of reactive oxygen intermediates. Our findings suggest that MenSCs modulate the macrophage population and that this modulation must be taken into consideration when it comes to future clinical applications