Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated MSCs Recruitment and Histone Acetylation-Mediated Osteogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus Rattus norvegicus
PROVIDER: GSE236135 | GEO | 2024/02/15
REPOSITORIES: GEO
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Project description:Cranial bone defect is a major clinical challenge that increases the life burden of patients. Tricarboxylic acid (TCA) cycle metabolites have recently drawn considerable attention in the field of bone tissue regeneration due to their bio-safety, low cost, structural stability, and effectiveness. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration via a facile and general approach remains lacking. Moreover, the mechanism underlying the release of TCA cycle metabolites from biomaterials in immune responses and mesenchymal stem cells (MSCs) fate (migration and differentiation) remain unknown. Herein, inspired by the Hofmeister effects, we developed a series of TCA metabolite (in the form of sodium salt)-coordinated biomimetic hydrogels (CGG) with strong mechanical and anti-swelling performances. Importantly, the sodium citrate (Na3Cit)-treated CGG hydrogels (CGG-Cit) with the highest mechanical modulus and strength significantly promoted skull bone regeneration in rats and mice. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, we demonstrated that CGG-Cit promotes Gli1+ MSCs migration via neutrophil-secreted OSM. Our results also indicate that CGG-Cit improved osteogenesis via enhanced H3K9ac modification on osteogenic master genes. Taken together, the immune microenvironments and MSCs fate-regulated biomimetic hydrogels developed herein represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.
2024-02-15 | GSE236134 | GEO
Project description:Cranial bone defect is a major clinical challenge that increases the life burden of patients. Tricarboxylic acid (TCA) cycle metabolites have recently drawn considerable attention in the field of bone tissue regeneration due to their bio-safety, low cost, structural stability, and effectiveness. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration via a facile and general approach remains lacking. Moreover, the mechanism underlying the release of TCA cycle metabolites from biomaterials in immune responses and mesenchymal stem cells (MSCs) fate (migration and differentiation) remain unknown. Herein, inspired by the Hofmeister effects, we developed a series of TCA metabolite (in the form of sodium salt)-coordinated biomimetic hydrogels (CGG) with strong mechanical and anti-swelling performances. Importantly, the sodium citrate (Na3Cit)-treated CGG hydrogels (CGG-Cit) with the highest mechanical modulus and strength significantly promoted skull bone regeneration in rats and mice. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, we demonstrated that CGG-Cit promotes Gli1+ MSCs migration via neutrophil-secreted OSM. Our results also indicate that CGG-Cit improved osteogenesis via enhanced H3K9ac modification on osteogenic master genes. Taken together, the immune microenvironments and MSCs fate-regulated biomimetic hydrogels developed herein represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.
2024-02-15 | GSE235943 | GEO
Project description:Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated MSCs Recruitment and Histone Acetylation-Mediated Osteogenesis
| PRJNA989116 | ENA
Project description:Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated MSCs Recruitment and Histone Acetylation-Mediated Osteogenesis [scRNA-Seq]
| PRJNA988066 | ENA
Project description:Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated MSCs Recruitment and Histone Acetylation-Mediated Osteogenesis [RNA-Seq]
| PRJNA989120 | ENA
Project description:Rapid neutrophil recruitment to sites of inflammation is crucial for innate immune responses. Here, we reveal that the G-protein-coupled receptor GPR35 is upregulated in activated neutrophils, and it promotes their migration. GPR35-deficient neutrophils are less recruited from blood vessels into inflamed tissue, and the mice are less efficient in clearing peritoneal bacteria. Using a bioassay, we find that serum and activated platelet supernatant stimulate GPR35, and we identify the platelet-derived serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) as a GPR35 ligand. GPR35 function in neutrophil recruitment is strongly dependent on platelets, with the receptor promoting transmigration across platelet-coated endothelium. Mast cells also attract GPR35+ cells via 5-HIAA. Mice deficient in 5-HIAA show a loss of GPR35-mediated neutrophil recruitment to inflamed tissue. These findings identify 5-HIAA as a GPR35 ligand and neutrophil chemoattractant and establish a role for platelet- and mast cell-produced 5-HIAA in cell recruitment to the sites of inflammation and bacterial clearance.
| S-EPMC9037118 | biostudies-literature
Project description:The rapid growth of the brain in the first few years of life drives the expansion of the cranial vault. This expansion occurs primarily at the cranial sutures; premature fusion of these results in growth restriction perpendicular to the axis of the suture. The result of this is physical deformation of the cranial and facial skeleton, as well as the distortion of the underling brain and its physiology. These patients can present with symptoms of raised intracranial pressure, neurodevelopmental delay, as well as the morphological features of craniosynostosis. Acquired conditions such as the slit ventricle syndrome may also result in cephalocranial disproportion with these clinical features. Traditional vault remodeling surgery is able to correct the physical abnormalities as well as correcting cephalocranial disproportion. Its limitations include the degree of scalp expansion achievable as well as resulting defects in the bone. The use of distraction osteogenesis of the cranial vault permits a controlled expansion in a predetermined vector in a gradual manner. When used in the calvarium, this combines the benefits of tissue expansion on the scalp, as well as stimulating the production of new bone, reducing the defects resulting from expansion. In this review, the authors describe some of the surgical considerations important to the use of this technique. This includes the relevant anatomy and technical aspects illustrated with the use of clinical cases. Finally, they present a summary of their experience and discuss the complications associated with cranial vault distraction osteogenesis.
| S-EPMC4219914 | biostudies-other
Project description:BackgroundHere we provide the most comprehensive study to date on the cranial ossification sequence in Lipotyphla, the group which includes shrews, moles and hedgehogs. This unique group, which encapsulates diverse ecological modes, such as terrestrial, subterranean, and aquatic lifestyles, is used to examine the evolutionary lability of cranial osteogenesis and to investigate the modularity of development.ResultsAn acceleration of developmental timing of the vomeronasal complex has occurred in the common ancestor of moles. However, ossification of the nasal bone has shifted late in the more terrestrial shrew mole. Among the lipotyphlans, sequence heterochrony shows no significant association with modules derived from developmental origins (that is, neural crest cells vs. mesoderm derived parts) or with those derived from ossification modes (that is, dermal vs. endochondral ossification).ConclusionsThe drastic acceleration of vomeronasal development in moles is most likely coupled with the increased importance of the rostrum for digging and its use as a specialized tactile surface, both fossorial adaptations. The late development of the nasal in shrew moles, a condition also displayed by hedgehogs and shrews, is suggested to be the result of an ecological reversal to terrestrial lifestyle and reduced functional importance of the rostrum. As an overall pattern in lipotyphlans, our results reject the hypothesis that ossification sequence heterochrony occurs in modular fashion when considering the developmental patterns of the skull. We suggest that shifts in the cranial ossification sequence are not evolutionarily constrained by developmental origins or mode of ossification.
| S-EPMC3247175 | biostudies-literature
Project description:The interaction between neutrophils and endothelial cells is critical for the pathogenesis of vascular inflammation. However, the regulation of neutrophil adhesive function remains not fully understood. Intravital microscopy demonstrates that neutrophil DREAM promotes neutrophil recruitment to sites of inflammation induced by TNF-α but not MIP-2 or fMLP. We observe that neutrophil DREAM represses expression of A20, a negative regulator of NF-κB activity, and enhances expression of pro-inflammatory molecules and phosphorylation of IκB kinase (IKK) after TNF-α stimulation. Studies using genetic and pharmacologic approaches reveal that DREAM deficiency and IKKβ inhibition significantly diminish the ligand-binding activity of β2 integrins in TNF-α-stimulated neutrophils or neutrophil-like HL-60 cells. Neutrophil DREAM promotes degranulation through IKKβ-mediated SNAP-23 phosphorylation. Using sickle cell disease mice lacking DREAM, we show that hematopoietic DREAM promotes vaso-occlusive events in microvessels following TNF-α challenge. Our study provides evidence that targeting DREAM might be a novel therapeutic strategy to reduce excessive neutrophil recruitment in inflammatory diseases.
| S-EPMC8719643 | biostudies-literature
Project description:BackgroundChemokines contribute to inflammatory responses by inducing leukocyte migration and extravasation. In addition, chemoattractants other than classical chemokines can also be present. Many chemokines have been demonstrated to cooperate, leading to an augmentation in leukocyte recruitment and providing a potential role for the presence of multiple chemoattractants. Extracellular cyclophilins are a group of alternative chemotactic factors, which can be highly elevated during various inflammatory responses and, as we have previously shown, can contribute significantly to neutrophil recruitment in an animal model of acute lung inflammation. In the current studies we investigated whether the most abundant extracellular cyclophilin, CypA, has the capacity to function in partnership with 2 classical chemokines known to be secreted in the same model, macrophage inflammatory protein (MIP)-2/CXCL2 and keratinocyte chemoattractant (KC)/CXCL1.MethodsNeutrophil migration in response to combinations of CypA and MIP-2 or CypA and KC was measured by in vitro chemotaxis assays. Biochemical responses of neutrophils incubated with the combinations of chemoattractants were determined by changes in chemokine receptor internalization and actin polymerization measured by flow cytometry, and changes in intracellular calcium mobilization measured with a calcium sensitive fluorochrome.ResultsA combination of CypA and MIP-2, but not KC, augmented neutrophil migration. Based on the level of augmentation, the cooperation between CypA and MIP-2 appeared to be synergistic. Evidence that CypA and MIP-2 cooperate at the biochemical level was demonstrated by increases in receptor internalization, calcium mobilization, and actin polymerization.ConclusionThese findings provide evidence for the capacity of extracellular cyclophilins to interact with classical chemokines, resulting in greater and more efficient leukocyte recruitment.
| S-EPMC3218749 | biostudies-literature