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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.04.551608v1?rss=1

Authors: Gomez-Ferrer, M., Amaro-Prellezo, E., Albiach-Delgado, A., Ten-Domenech, I., Kuligowski, J., Sepulveda, P.

Abstract:
Premature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. We isolated HM sEVs from HM samples and analyzed their oxylipin content using liquid chromatography coupled to mass spectrometry, which revealed the presence of anti-inflammatory oxylipins. We then examined the efficacy of a mixture of these oxylipins in combating inflammation and fibrosis, in vitro and and in a murine model of inflammatory bowel disease (IBD). HM-related sEVs contained higher concentrations of oxylipins derived from docosahexaenoic acid, an omega-3 fatty acid. Three anti-inflammatory oxylipins, 14-HDHA, 17-HDHA, and 19,20-DiHDPA ({omega}3 OXLP), demonstrated similar efficacy to HM sEVs in preventing cell injury, inducing re-epithelialization, mitigating fibrosis, and modulating immune responses. Both {omega}3 OXLP and HM sEVs effectively reduced inflammation in IBD-model mice, preventing colon shortening, infiltration of inflammatory cells and tissue fibrosis. Incorporating this unique cocktail of oxylipins into fortified milk formulas might reduce the risk of NEC in PIs and also provide immunological and neurodevelopmental support.

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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.03.551824v1?rss=1

Authors: Qin, K., Wu, X.

Abstract:
The nuclear mitochondrial DNA (NUMT) is found in cancer cells, but the mitochondrial DNAs entering the nuclei in normal cells have not been captured. Here, we utilized super-resolution optical imaging to capture the phenomenon by the probe PicoGreen and found mitochondrial DNAs and mitochondria accumulated in the nucleoli by four probes and overexpressing the MRPL58-DsRed. Our results provide an new explanation for mtDNA carryover and lay the foundation for the involvement of nuclear export of nucleoli in de novo mitochondrial biogenesis in another of our unpublished articles.

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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.02.551383v1?rss=1

Authors: Cohen, M. L., Brumwell, A. N., Ho, T. C., Montas, G., Golden, J. A., Jones, K. D., Wolters, P. J., Wei, Y., Chapman, H. A., Le Saux, C. J.

Abstract:
Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate this, we administered the fibroblast-selective TGF{beta}1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Unexposed biopsy samples showed higher fibroblast TGF{beta}1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG significantly downregulated TGF{beta}1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted Frizzle-like Receptor Protein 2 (sFRP2), an unrecognized TGF{beta}1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s). In human AEC2-fibroblast coculture organoids, sFRP2 was essential for AEC2 trans-differentiation to basal cells. Precision cut lung slices (PCLS) from normal donors demonstrated that TGF{beta}1 promoted KRT17 expression and AEC2 morphological change, while sFRP2 was necessary for KRT5 expression in AEC2-derived basaloid cells. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin-related signaling in AEC2s were required for sFRP2-induced KRT5 expression. These findings highlight stage-specific TGF{beta}1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify the TGF{beta}1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.

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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.04.552008v1?rss=1

Authors: Talavera, R. A., Prichard, B. E., Sommer, R. A., Leitao, R. M., Sarabia, C. J., Hazir, S., Paulo, J. A., Gygi, S., Kellogg, D.

Abstract:
Cell growth is required for cell cycle progression. The amount of growth required for cell cycle progression is reduced in poor nutrients, which leads to a reduction in cell size. In budding yeast, nutrients influence cell size by modulating the duration and extent of bud growth, which occurs predominantly in mitosis. However, the mechanisms are unknown. Here, we used mass spectrometry to identify proteins that mediate the effects of nutrients on bud growth. This led to the discovery that nutrients regulate numerous components of the Mitotic Exit Network (MEN), which controls exit from mitosis. A key component of the MEN undergoes gradual multi-site phosphorylation during bud growth that is dependent upon growth and correlated with the extent of growth. Furthermore, activation of the MEN is sufficient to over-ride a growth requirement for mitotic exit. The data suggest a model in which the MEN integrates signals regarding cell growth and nutrient availability to ensure that mitotic exit occurs only when sufficient growth has occurred.

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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.02.551232v1?rss=1

Authors: Nguyen, T. P., Otani, T., Tsutsumi, M., Fujiwara, S., Nemoto, T., Fujimori, T., Furuse, M.

Abstract:
Epithelia must be able to resist mechanical force to preserve tissue integrity. While intercellular junctions are known to be important for the mechanical resistance of epithelia, the roles of tight junctions (TJs) remain to be established. We previously demonstrated that epithelial cells devoid of the TJ membrane proteins claudins and JAM-A completely lack TJs and exhibit focal breakages of their apical junctions. Here, we demonstrate that apical junctions undergo spontaneous fracture when claudin/JAM-A-deficient cells are exposed to mechanical stress. The junction fracture was accompanied by actin disorganization, and actin polymerization was required for apical junction integrity in the claudin/JAM-A-deficient cells. Further deletion of CAR resulted in the disruption of ZO-1 molecule ordering at cell junctions, accompanied by severe defects in apical junction integrity. These results demonstrate that TJ membrane proteins regulate the mechanical resistance of the apical junctional complex in epithelial cells.

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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.04.551943v1?rss=1

Authors: Bagley, D. C., Russell, T., Ortiz-Zapater, E., Fox, K., Redd, P. F., Joseph, M., Rice, C. D., Reilly, C. A., Parsons, M., Rosenblatt, J.

Abstract:
Asthma is a common disease characterized by airway constriction, excess mucus, and inflammation. Although asthma is an inflammatory disease, subclassed by different endotypes, triggers, and immune responses, the defining diagnostic symptom is mechanical bronchoconstriction from uncontrolled smooth muscle contraction. We previously discovered a conserved process that drives epithelial cell death in response to mechanical cell crowding called epithelial cell extrusion (1,2). Because modest crowding triggers extrusion to maintain constant homeostatic epithelial cell densities, we reasoned that the pathological crowding from bronchoconstriction might potentially destroy the airway epithelial barrier, causing the typical inflammatory period that follows an asthma attack. Here, using immune-primed mice, we show that the crowding of bronchoconstriction causes excess epithelial cell extrusion and damage, resulting in inflammation in distal airways, and mucus secretion in proximal airways. Surprisingly, relaxing airways following bronchoconstriction with the current rescue treatment, albuterol, did not prevent epithelial extrusion and destruction, inflammation, or mucus secretion. However, inhibiting canonical live cell extrusion signaling during bronchoconstriction with stretch-activated/TRP channel or sphingosine 1-phosphate (S1P) inhibitors blocked all downstream symptoms. Our findings propose a new etiology for asthma where the extreme mechanical crowding from a bronchoconstrictive attack causes inflammation by wounding airway epithelium. Whereas most therapies focus on modulating downstream inflammatory symptoms, our studies suggest that blocking epithelial extrusion could prevent the feed-forward asthma inflammatory cycle.

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