Single-cell RNA sequencing and spatial transcriptomics reveal the osteoimmune microenvironment of biomaterial-mediated bone regeneration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246476 | GEO | 2024/06/30
REPOSITORIES: GEO
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Project description:The bone-defect-repair process involves complex interaction between mesenchymal stem cells (MSCs) and immune cells, while the heterogeneity of osteoimmune microenvironment around implanted biomaterials remains elusive. By combining analysis of scRNA-seq and spatial transcriptomics technologies, we revealed that MgphiMSCs subpopulation served as the pioneers during the early stage of biomaterials-mediated bone defect healing process. They performed efficient osteogenic differentiation potential and had close interactions with immune cells. Remarkably, the MgphiMSCs could response to biomaterials-mediated osteoimmune microenvironment, rewired the polarization and osteoclastic differentiation of macrophages via midkine (MDK) signaling pathway. The inhibition of MDK activated the pro-inflammatory programs of macrophages and osteoclastogenesis. Meanwhile, multiple innate and adaptive immune-cell subsets exhibited close crosstalk between MgphiMSCs via SPP1 signaling pathway. These cellular profiles and interactions characterized in this study could broaden our understanding of the functional MSCs subpopulations at the early stage of biomaterial-mediated bone regeneration and provide the basis for the materials-designed strategies that target osteoimmune modulation.
2024-06-30 | GSE246475 | GEO
Project description:The bone-defect-repair process involves complex interaction between mesenchymal stem cells (MSCs) and immune cells, while the heterogeneity of osteoimmune microenvironment around implanted biomaterials remains elusive. By combining analysis of scRNA-seq and spatial transcriptomics technologies, we revealed that MgphiMSCs subpopulation served as the pioneers during the early stage of biomaterials-mediated bone defect healing process. They performed efficient osteogenic differentiation potential and had close interactions with immune cells. Remarkably, the MgphiMSCs could response to biomaterials-mediated osteoimmune microenvironment, rewired the polarization and osteoclastic differentiation of macrophages via midkine (MDK) signaling pathway. The inhibition of MDK activated the pro-inflammatory programs of macrophages and osteoclastogenesis. Meanwhile, multiple innate and adaptive immune-cell subsets exhibited close crosstalk between MgphiMSCs via SPP1 signaling pathway. These cellular profiles and interactions characterized in this study could broaden our understanding of the functional MSCs subpopulations at the early stage of biomaterial-mediated bone regeneration and provide the basis for the materials-designed strategies that target osteoimmune modulation.
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Project description:Single-cell RNA sequencing and spatial transcriptomics reveal the osteoimmune microenvironment of biomaterial-mediated bone regeneration
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Project description:Activating autologous stem cells after the implantation of biomaterials is an important process to initiate bone regeneration. Although several studies have demonstrated the mechanism of biomaterial-mediated bone regeneration, a comprehensive single-cell level transcriptomic map revealing the influence of biomaterials on regulating the temporal and spatial expression patterns of mesenchymal stem cells (MSCs) is still lacking. Herein, the osteoimmune microenvironment is depicted around the classical collagen/nanohydroxyapatite-based bone repair materials via combining analysis of single-cell RNA sequencing and spatial transcriptomics. A group of functional MSCs with high expression of matrix Gla protein (Mgp) is identified, which may serve as a pioneer subpopulation involved in bone repair. Remarkably, these Mgp high-expressing MSCs (MgphiMSCs) exhibit efficient osteogenic differentiation potential and orchestrate the osteoimmune microenvironment around implanted biomaterials, rewiring the polarization and osteoclastic differentiation of macrophages through the Mdk/Lrp1 ligand-receptor pair. The inhibition of Mdk/Lrp1 activates the pro-inflammatory programs of macrophages and osteoclastogenesis. Meanwhile, multiple immune-cell subsets also exhibit close crosstalk between MgphiMSCs via the secreted phosphoprotein 1 (SPP1) signaling pathway. These cellular profiles and interactions characterized in this study can broaden the understanding of the functional MSC subpopulations at the early stage of biomaterial-mediated bone regeneration and provide the basis for materials-designed strategies that target osteoimmune modulation.
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Project description:Single-cell RNA sequencing and spatial transcriptomics reveal the osteoimmune microenvironment of biomaterial-mediated bone regeneration [scRNA-seq]
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Project description:Single-cell RNA sequencing and spatial transcriptomics reveal the osteoimmune microenvironment of biomaterial-mediated bone regeneration [ST-seq]
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Project description:The effective treatment of advanced cervical cancer remains challenging. Herein, single-nucleus RNA sequencing (snRNA-seq) and SpaTial enhanced resolution omics-sequencing (Stereo-seq) are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC). The expression levels of most immune suppressive genes in the tumor and inflammation areas of CSCC are not significantly higher than those in the non-cancer samples, except for LGALS9 and IDO1. Stronger signals of CD56+ NK cells and immature dendritic cells are found in the hypermetabolic tumor areas, whereas more eosinophils, immature B cells, and Treg cells are found in the hypometabolic tumor areas. Moreover, a cluster of pro-tumorigenic cancer-associated myofibroblasts (myCAFs) are identified. The myCAFs may support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling of the tumor extracellular matrix. Furthermore, these myCAFs are associated with poorer survival probability in patients with CSCC, predict resistance to immunotherapy, and might be present in a small fraction (< 30%) of patients with advanced cancer. Immunohistochemistry and multiplex immunofluorescence staining are conducted to validate the spatial distribution and potential function of myCAFs. Collectively, these findings enhance the understanding of the immunological microenvironment of CSCC and shed light on the treatment of advanced CSCC.
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Project description:The design of orthopedic biomaterials has gradually shifted from "immune-friendly" to "immunomodulatory," in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration. Despite the well-known effects of bioactive metallic ions on osteogenesis, how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied. Herein, we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation (Mg2+) in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid (PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions. The results suggest that the Mg2+-controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory (IL-10) and pro-osteogenic (BMP-2 and TGF-β1) cytokines production. It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. The in vivo results further verify that a large amount of bony tissue, with comparable bone mineral density and mechanical properties, has been generated at an early post-surgical stage in rat intramedullary bone defect models. This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment.
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Project description:BackgroundCoordination between osteo-/angiogenesis and the osteoimmune microenvironment is essential for effective bone repair with biomaterials. As a highly personalized and precise biomaterial suitable for repairing complex bone defects in clinical practice, it is essential to endow 3D-printed scaffold the above key capabilities.ResultsHerein, by introducing xonotlite nanofiber (Ca6(Si6O17) (OH)2, CS) into the 3D-printed silk fibroin/gelatin basal scaffold, a novel bone repair system named SGC was fabricated. It was noted that the incorporation of CS could greatly enhance the chemical and mechanical properties of the scaffold to match the needs of bone regeneration. Besides, benefiting from the addition of CS, SGC scaffolds could accelerate osteo-/angiogenic differentiation of bone mesenchymal stem cells (BMSCs) and meanwhile reprogram macrophages to establish a favorable osteoimmune microenvironment. In vivo experiments further demonstrated that SGC scaffolds could efficiently stimulate bone repair and create a regeneration-friendly osteoimmune microenvironment. Mechanistically, we discovered that SGC scaffolds may achieve immune reprogramming in macrophages through a decrease in the expression of Smad6 and Smad7, both of which participate in the transforming growth factor-β (TGF-β) signaling pathway.ConclusionOverall, this study demonstrated the clinical potential of the SGC scaffold due to its favorable pro-osteo-/angiogenic and osteoimmunomodulatory properties. In addition, it is a promising strategy to develop novel bone repair biomaterials by taking osteoinduction and osteoimmune microenvironment remodeling functions into account.
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