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Identification of omega-3 oxylipins in human milk-derived extracellular vesicles with pro-resolutive actions in gastrointestinal inflammation.
Saturday, August 5, 2023 • Duration
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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Super-resolution optical imaging reveals accumulation of small mitochondria in the nucleoli of mouse embryos and stem cells
Saturday, August 5, 2023 • Duration
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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A fibroblast-derived TGFβ/sFRP2 noncanonical Wnt signaling axis underlies epithelial metaplasia in idiopathic pulmonary fibrosis
Saturday, August 5, 2023 • Duration
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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Cell growth and nutrient availability control the mitotic exit signaling network in budding yeast
Friday, August 4, 2023 • Duration
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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Tight junction membrane proteins regulate the mechanical resistance of the apical junctional complex
Friday, August 4, 2023 • Duration
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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The mechanics of bronchoconstriction cause airway epithelial damage and inflammation by excess crowding-induced extrusion
Friday, August 4, 2023 • Duration
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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RBL2 represses the transcriptional activity of Multicilin to inhibit multiciliogenesis
Friday, August 4, 2023 • Duration
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.04.551992v1?rss=1
Authors: Quiroz, E. J., Kim, S., Gautam, L. K., Borok, Z., Kintner, C., Ryan, A. L.
Abstract:
A core pathophysiologic feature underlying many respiratory diseases is multiciliated cell dysfunction, leading to inadequate mucociliary clearance. Due to the prevalence and highly variable etiology of mucociliary dysfunction in respiratory diseases, it is critical to understand the mechanisms controlling multiciliogenesis that may be targeted to restore functional mucociliary clearance. Multicilin, in a complex with E2F4, is necessary and sufficient to drive multiciliogenesis in airway epithelia, however this does not apply to all cell types, nor does it occur evenly across all cells in the same cell population. In this study we further investigated how co-factors regulate the ability of Multicilin to drive multiciliogenesis. Combining data in mouse embryonic fibroblasts and human bronchial epithelial cells, we identify RBL2 as a repressor of the transcriptional activity of Multicilin. Knockdown of RBL2 in submerged cultures or phosphorylation of RBL2 in response to apical air exposure, in the presence of Multicilin, allows multiciliogenesis to progress. These data demonstrate a dynamic interaction between RBL2 and Multicilin that regulates the capacity of cells to differentiate and multiciliate. Identification of this mechanism has important implications for facilitating MCC differentiation in diseases with impaired mucociliary clearance.
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Optogenetic control of lysosome function
Friday, August 4, 2023 • Duration
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.02.551716v1?rss=1
Authors: Ilyinsky, N. S., Bukhalovich, S. M., Bagaeva, D. F., Nesterov, S. V., Alekseev, A. A., Tsybrov, F. M., Bogorodskiy, A. O., Moiseeva, O. V., Vlasova, A. D., Kovalev, K. V., Mikhailov, A. E., Rogachev, A. V., Bamberg, E., Ivanovich, V., Borshchevskiy, V. I.
Abstract:
Lysosome protective, metabolic, signaling functions are highly dependent on their pH. A lack of tools of high spatial and temporal resolution for pH control is a bottleneck of lysosome related cell research. Light-driven inward proton pump NsXeR, targeted to the lysosomes of mammalian cells, produces lysosome alkalization simply by light. Complementary use of outward proton pumping Arch3 rhodopsins in lysosomes offers an approach to vary pH in a range from around 5 to 6.5 in both directions (alkalization and acidification). Lyso-NsXeR optogenetics efficiency was demonstrated, in particular, by its ability to inhibit lysosome proteolytic enzymes. Unprecedented time resolution of the optogenetic approach allowed direct in situ monitoring of vATPase activity. Thus, optogenetic monitoring and regulation of the lysosome function, through pH control over a wide range, could serve as an approach to studying fundamental cell processes, and rational drug design.
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Multi-color live-cell optical nanoscopy using phasor analysis
Friday, August 4, 2023 • Duration
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.04.551988v1?rss=1
Authors: Zhang, Z., Huang, Y., Tao, W., Wei, Y., Xu, L., Gong, W., Zhang, Y., Han, Y., Kuang, C., Liu, X.
Abstract:
Stimulated emission depletion microscopy (STED) is a powerful tool for studying nanoscale cell structure and activity, but the difficulties it encounters in multicolor imaging limit its application in biological research. To overcome the disadvantages of limited number of channels and high cost of multicolor STED imaging based on spectral identity, we introduced lifetime into live-cell multicolor STED imaging by separating selected dyes of the same spectrum by phasor analysis. Experimental results show that our method enables live-cell STED imaging with at least 4 colors, enabling observation of cellular activity beyond the diffraction limit.
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Positive feedback regulation of Pparγ1sv and Pparγ2 during adipogenesis in 3T3-L1 cells
Friday, August 4, 2023 • Duration
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.08.03.551916v1?rss=1
Authors: Takenaka, Y., Kakinuma, Y., Inoue, I.
Abstract:
We have previously identified the novel splicing variant of mouse Ppar{gamma} (Ppar{gamma}1sv) and proposed the synergistic regulation of the early stage of adipocyte differentiation by Ppar{gamma}1sv and Ppar{gamma}2. Here, we report the finding of PPAR{gamma}-binding sites within the Ppar{gamma} gene locus and its importance in adipogenesis and propose the positive feedback regulation of Ppar{gamma}1sv and Ppar{gamma}2 expression during the adipocyte differentiation of 3T3-L1 cells.
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