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An organ-specific angiogenic control mechanism for endothelial tailoring.

ABSTRACT: Each organ of the human body requires locally-adapted blood vessels1–3. The gain of such organotypic vessel specializations is often deemed molecularly unrelated to the process of organ vascularization. Opposing this model, we reveal a molecular mechanism for brain-specific angiogenesis that operates under the control of Wnt7a/b ligands, well-known blood-brain barrier maturation signals4–6. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25 in brain endothelial cells. This hitherto poorly characterized GPI-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane which lines the brain surface, and whose distinctive molecular composition is controlled by embryonic pial fibroblasts. Mechanistically, Mmp25 confers brain invasive competence by cleaving the pial basement membrane-enriched Col4a5/6 within a short non-collagenous region of the central helical part of the heterotrimer. Upon genetic interference with pial basement membrane composition, the Wnt/β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in a properly patterned, yet blood-brain barrier-defective cerebrovasculature. This work reveals an organ-specific angiogenesis mechanism, sheds light on tip cell mechanistic angiodiversity, and thereby illustrates how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Placenta, Trophoblast Cell

SUBMITTER: Marc Dieu

LAB HEAD: Benoit Vanhollebeke

PROVIDER: PXD042613 | Pride | 2024-02-08

REPOSITORIES: Pride

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An organ-specific angiogenic control mechanism for endothelial tailoring

Project description:Each organ of the human body requires locally-adapted blood vessels. The gain of such organotypic vessel specializations is often deemed molecularly unrelated to the process of organ vascularization. Opposing this model, we reveal a molecular mechanism for brain-specific angiogenesis, that operates under the control of Wnt7a/b ligands, well-known blood-brain barrier maturation signals. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25 in brain endothelial cells. This hitherto poorly characterized GPI-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane lining the brain surface, which distinctive molecular composition is controlled by embryonic pial fibroblasts. Mechanistically, Mmp25 confers brain invasive competence by cleaving the pial basement membrane-enriched Col4a5/6 within a short non-collagenous region of the central helical part of the heterotrimer. Upon genetic interference with pial basement membrane composition, the Wnt/β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in properly patterned, yet blood-brain barrier-defective cerebrovasculatures. This work reveals an organ-specific angiogenesis mechanism, sheds light on tip cell mechanistic angiodiversity, and thereby illustrates how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.

2024-02-08 | GSE233662 | GEO

Endogenous TOM20 proximity labelling: a Swiss-knife for the study of mitochondrial proteins in human cells

Project description:The majority of mitochondrial proteins are encoded by the nuclear genome and must be imported into the mitochondria. There are two main paths for mitochondrial protein import: post-translational and co-translational import. Co-translational import couples the translation and the translocation of the mitochondrial proteins, alleviating the energy cost typically associated with the post-translational import relying on chaperone systems. The mitochondrial co-translational import mechanisms are still unclear with few actors identified but none have been described in mammals yet. We thus profiled the TOM20 proxisome using BioID, assuming that some of identified proteins could be molecular actors of the co-translational import in human cells. The obtained results showed a high enrichment of RNA binding proteins close to the TOM complex. However, for the few selected candidates, we could not demonstrate a role in the mitochondrial co-translational import process. Nonetheless, we were able to demonstrate a new mitochondrial localization for nuclear proteins. Besides, additional analyses revealed a negative correlation between the abundance of mitochondrial proteins and their reported half-life. This experimental approach is thus proposed to potentially characterize mitochondrial co-translational import effectors in human cells and to monitor protein entry inside mitochondria with a potential application in the prediction of mitochondrial protein half-life.

2023-07-20 | PXD038821 | Pride

A cytoplasmic chemoreceptor and Reactive Oxygen Species mediate bacterial chemotaxis to copper

Project description:Chemotaxis is a widespread strategy used by unicellular and multicellular living organisms to maintain their fitness in stressful environments. We previously showed that bacteria can trigger a negative chemotactic response to a copper (Cu)-rich environment. Cu ions toxicity on bacterial cell physiology has been mainly linked to mismetallation events and ROS production, although the precise role of Cu-generated ROS remains largely debated. Here, we found that the cytoplasmic Cu ions content mirrors variations of the extracellular Cu ions concentration and triggers a dose-dependent oxidative stress, which can be abrogated by superoxide dismutase and catalase overexpression. The inhibition of ROS production in the cytoplasm not only improves bacterial growth but also impedes Cu-chemotaxis, indicating that ROS derived from cytoplasmic Cu ions mediate the control of bacterial chemotaxis to Cu. We also identified the Cu chemoreceptor McpR, which binds Cu ions with low affinity, suggesting a labile interaction. In addition, we demonstrate that the cysteine 75 and histidine 99 within the McpR sensor domain are key residues in Cu chemotaxis and Cu coordination. Finally, we discovered that in vitro both Cu(I) and Cu(II) ions modulate McpR conformation in a distinct manner. Overall,our study provides mechanistic insights on a redox-based control of Cu chemotaxis, indicating that the cellular redox status can play a key role in bacterial chemotaxis.

2023-09-05 | PXD044512 | Pride

Horizontal acquisition of a DNA ligase improves DNA damage tolerance in eukaryotes

Project description:Bdelloid rotifers are part of the restricted circle of multicellular animals that can withstand a wide range of genotoxic stresses at any stage of their life cycle. In this study, bdelloid rotifer Adineta vaga was used as a model to decipher the molecular basis of their extreme tolerance. Proteomic analysis showed that a specific DNA ligase, different from those usually involved in DNA repair in eukaryotes, is strongly over-represented upon ionizing radiation. A phylogenetic analysis revealed its orthology to prokaryotic DNA ligase E, and its horizontal acquisition by bdelloid rotifers and plausibly other eukaryotes. The fungus Mortierella verticillata, having a single copy of this DNA Ligase E homolog, also exhibits an increased radiation tolerance with an over-expression of this DNA ligase E following X-ray exposure. We also provide evidence that A. vaga ligase E is a major contributor of DNA breaks ligation activity, which is a common step of all important DNA repair pathways. Consistently, its heterologous expression in human cell lines significantly improved their radio-tolerance. Overall, this study highlights the potential of horizontal gene transfers in eukaryotes, and their contribution to the adaptation to extreme conditions.

2024-01-24 | PXD043051 | Pride

Quantitative phosphoproteomics reveals SnRK1-dependent phosphosites in rice sheaths during grain filling

Project description:Insufficient leaf photosynthesis promotes sheath NSC transport to the panicle during grain filling. SnRK1 regulates assimilate distribution between plant tissues and organs. However, the mechanism by which SnRK1 regulates sheath NSC transport to the panicle and its response to limited leaf assimilation remain unclear. Here, we performed leaf cutting (LC) at anthesis to simulate insufficient leaf assimilation and set no treatment as a CK. In response to LC, SnRK1 activity increased rapidly, and NSC transport was advanced. Sheath NSCs were not transported in a snrk1a mutant with deficient SnRK1 activity. These results indicated that SnRK1 activity is important for sheath NSC transport. The high correlation of T6P and sucrose and the inhibition of SnRK1 by T6P in sheaths in vitro implied that T6P slightly inhibits SnRK1 activity in rice sheaths in response to sucrose availability. The increase in SnRK1 activity was accompanied by an increase in OsSnRK1a expression and a low sucrose content. Low sucrose signaling increases SnRK1 transcription. Therefore, we speculated that OsSnRK1a expression positively regulates SnRK1 activity in response to low sucrose availability in rice sheaths. Through phosphoproteomics and further PRM verification, 20 phosphosites that depend on SnRK1 and are correlated with NSC transport were obtained. Based on the function of these sites and proteins, we found that SnRK1 regulates starch degradation, sucrose metabolism, phloem transport, sugar transport across tonoplast, and glycolysis via phosphorylation to promote sheath NSC transport. Overall, our results revealed the importance, function and regulatory mechanism of SnRK1 in sheath NSC transport.

2022-03-18 | PXD024675 | Pride

Quantitative proteomics reveals SnRK1-dependent protein in rice sheaths during grain filling

2022-03-18 | PXD024670 | Pride

Equine muscle-derived mesenchymal stem cells protect cartilage explants in osteoarthritis model: secretome characterization

Project description:Background: Osteoarthritis is a highly prevalent joint degenerative disease for which therapeutic treatments are limited or invasive. Cell therapy based on mesenchymal stem/stromal cells (MSCs) is therefore seen as a promising approach for this disease, in both human and horses. Objective: As the regenerative potential of MSCs is mainly conferred by paracrine function, the goal of this study is to characterize the secretome of muscle-derived MSCs (mdMSCs) in an in vitro model of OA to evaluate the clinical interest of mdMSCs as cell therapy for joint diseases like osteoarthritis. Methods: An equine osteoarthritis model composed of cartilage explants exposed to pro-inflammatory cytokines was first developed. Then, the effects of mdMSC coculture on cartilage explant were studied by measuring the glycosaminoglycan release and the NO2- production. To identify the underlying molecular actors, SILAC-based secretome analyses were conducted, in the presence of serum. The relative abundance of highly sequenced proteins was finally confirmed by western blot. Results: Co-culture with muscle-derived MSCs decreases the cytokine-induced glycosaminoglycan release by cartilage explants, suggesting a protecting effect of mdMSCs. Among the 52 equine proteins sequenced in the co-culture medium, the abundance of decorin and matrix metalloproteinase 3 was modified, as confirmed by western blot analyses. Conclusions: These results suggest that muscle-derived MSCs could reduce the catabolic effect of TNF and IL-1 on cartilage explant by decreasing the secretion and activity of Matrix Metalloproteinase 3 and increasing the decorin secretion

2022-11-08 | PXD031924 | Pride

The global downregulation of protein synthesis observed during hepatogenic maturation is associated with a decrease in TOP mRNA translation The global downregulation of protein synthesis observed during hepatogenic maturation is associated with a decrease in TOP mRNA translation

Project description:Translational regulation is of paramount importance for proteome remodeling during stem cell differentiation both at the global and transcript-specific levels. In this study, we characterized translational remodeling during hepatogenic differentiation of induced pluripotent stem cells (iPSCs) by polysome profiling. We demonstrate that protein synthesis increases during exit from pluripotency, and is then globally repressed during later steps of hepatogenic maturation. This global downregulation of translation is accompanied by a decrease in the protein abundance of components of the translation machinery, which involves a global reduction in translational efficiency of terminal oligopyrimidine tract (TOP) mRNA encoding translation-related factors. Despite global translational repression during hepatogenic differentiation, key hepatogenic genes remain efficiently translated, and the translation of several transcripts involved in hepato-specific functions and metabolic maturation are even induced. We conclude that, during hepatogenic differentiation, a global decrease in protein synthesis is accompanied by a specific translational rewiring of hepato-specific transcripts.

2022-12-26 | PXD038204 | Pride

Extrinsic inflammatory, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation block in multiple sclerosis

Project description:Multiple sclerosis (MS) is the most frequent demyelinating disease and despite significant advances in the immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair process, represents a promising new treatment approach. However, spontaneous remyelination frequently fails in MS lesions due to an impaired differentiation of progenitor cells into mature, myelinating oligodendrocytes. Intrinsic oligodendroglial and extrinsic inflammatory factors may contribute to this differentiation block. Therefore, we compared induced pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) from MS patients and healthy controls as well as their response to extrinsic factors. While functional capabilities or proteome compostion of both cell types were virtually indistinguishable, we discovered that Interferon-gamma (IFNÎ³) producing immune cells significantly impaired oligodendroglial differentiation and observed no differences in the functional capabilities or the proteome. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors, but rather caused by the inflammatory environment present in MS lesions. These findings may contribute to the development of remyelination promoting strategies in MS.

2020-09-04 | PXD016043 | Pride

Identification of BNC2 interactors in human LX2 cells using RIME

Project description:The goal of this study was to use Rapid Immunoprecipitation Mass spectrometry of Endogenous protein (RIME) assays (Mohammed et al., 2016) to identify transcriptional regulatory partners of the transcription factor BNC2 in LX2 cells. Protein complexes were immune-precipitated with an anti-BNC2 antibody (55220-1-AP, Proteintech) or control non-immune IgG (normal rabbit IgG #2729, Cell Signaling) before being subjected to MS.

2022-08-05 | PXD003624 | Pride

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