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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.
2024-06-30 | GSE246096 | GEO
Project description:While cellular energy metabolism regulates tissue regeneration, it remains as a challenge with its limited understanding of activation by engineered scaffolds to regenerate tissue or organ for therapeutic purpose. This study presents a biosynthesized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [abbreviated as P(3HB-co-4HB)] and its major degradation product, 3-hydroxybutyrate (3HB), functioning as an endogenous bioenergetic molecule to facilitate bone regeneration and promote cellular anabolism via generations of adenosine triphosphate (ATP) and citrate that enhance the progression of human bone marrow mesenchymal stem cells (hBMSCs) towards osteoblastogenesis. Our studies demonstrate that 3HB not only significantly enhances in vitro ATP generation to elevate mitochondrial membrane potential (ΔΨm) and capillary-like tube formation, but also increases the content of intermediate metabolite, namely, citrate, in tricarboxylic acid (TCA) cycle, and ultimately promotes the formation of citrate-containing apatite during osteogenesis of hBMSCs. Furthermore, 3HB administration increases the bone mass in rats with ovariectomy (OVX)-induced osteoporosis. Results also show that the P(3HB-co-4HB) scaffold significantly enhances long-term induced bone repair in a rat model with critical-sized calvarial defects, compared to the commercialized available poly-L-lactic acid (PLLA) scaffold. Collectively, these findings uncover a previously undefined role of 3HB in promoting osteogenic differentiation of hBMSCs and highlight that the P(3HB-co-4HB) scaffold functions as a metabolically activated energetic material for bone regeneration.
2023-09-03 | GSE242022 | GEO
Project description:Biomaterial-based bone tissue engineering offers a promising prospect for the treatment of bone defects. In particular, the ability of biomaterials to regulate the immune microenvironment of the defect site is essential for effective bone regeneration. Electro-biomaterials have been confirmed to induce macrophage M2 polarization through metabolic pathways, thereby enhancing bone regeneration. Considering the central role of mitochondria in cellular metabolism and their ability to influence the function of neighboring cells through intercellular transfer, and inspired by the fact that tumor cells can uptake mitochondria from immune cells to generate energy, we hypothesize that the metabolic activation of immune cells by electro-materials can be transmitted to preosteoblasts through mitochondria to promote bone repair. Therefore, this study proposed a conductive micro-hydrogel (CMH) system composed of conductive hydrogel microspheres made from GelMA and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), which served as scaffolds for defect filling, and a biomimetic periosteum made from poly-l-lactic acid (PLLA) and polydopamine (PDA) for microsphere immobilization and isolation of soft tissue. The microspheres exhibited excellent tissue support and degradation properties, their high specific surface area enhanced tissue remodeling, and their good conductivity eliminated free radicals and induced macrophage M2 polarization, which were confirmed by tests of mechanical property, swelling and degradation, conductivity and assays of cellular biocompatibility, ROS generation, and macrophage phenotype. In vivo experiments using a rat mandibular defect model confirmed the excellent bone repair capabilities of the CMH system, and transcriptomics, metabolomics, and metabolic testing revealed that the CMH system upregulated the oxidative phosphorylation pathway of macrophage, enhancing mitochondrial respiration and ATP production. Mitochondrial tracing experiments demonstrated the transfer of macrophage mitochondria to preosteoblasts, resulting in enhanced metabolic activity and osteogenic differentiation of preosteoblasts. This study may be the first suggest that conductive biomaterials facilitate osteogenic immunomodulation through mitochondrial transfer, which provides a promising method for regulating the immune microenvironment and reveals a novel pathway by which M2 macrophages enhance osteogenesis.
2024-08-11 | GSE274088 | GEO
Project description:<p>Bone regeneration requires spatiotemporal coordination of immune modulation, stem cell recruitment, angiogenesis, and osteogenesis, yet most scaffolds lack sequential control across healing phases. We develop a near-infrared (NIR)-responsive therapeutic platform that integrates clinically available irradiation with an engineered 3D radially aligned nanofiber scaffold functionalized with black phosphorus (BP) and a bone marrow mesenchymal stem cell (BMSC)-targeting aptamer (Apt19S). NIR photothermal stimulation accelerates BP degradation, releasing phosphate ions and activating a heat-shock program to promote macrophage polarization, endogenous MSC homing, neovascularization, and osteogenic differentiation. Metabolomics reveals cooperative regulation of HSP-linked signaling and lipid metabolism. In a rat critical-size calvarial defect, the platform achieves robust bone regeneration without exogenous cells or growth factors. The system is simple, structurally tunable, and shape-customizable, providing a clinically translatable and modular framework for spatiotemporal microenvironment programming in bone and other regenerative settings.</p>
2026-03-04 | MTBLS13974 | MetaboLights
Project description:Single-cell RNA sequencing and spatial transcriptomics reveal the osteoimmune microenvironment of biomaterial-mediated bone regeneration
| PRJNA1033176 | ENA
Project description:The pathogenesis of osteoporosis (OP) is closely associated with the disrupted balance between osteogenesis and adipogenesis in bone marrow-derived mesenchymal stem cells (BMSCs). We analyzed published single-cell RNA sequencing (scRNA-seq) data to dissect the transcriptomic profiles of bone marrow-derived cells in OP, reviewing 56,377 cells across eight scRNA-seq datasets from femoral heads (osteoporosis or osteopenia n=5, osteoarthritis n=3). Seventeen genes, including carboxypeptidase M (CPM), were identified as key osteogenesis-adipogenesis regulators through comprehensive gene set enrichment, differential expression, regulon activity, and pseudotime analyses. In vitro, CPM knockdown reduced osteogenesis and promoted adipogenesis in BMSCs, while adenovirus-mediated CPM overexpression had the reverse effects. In vivo, intraosseous injection of CPM-overexpressing BMSCs mitigated bone loss in ovariectomized mice. Integrated scRNA-seq and bulk RNA sequencing analyses provided insight into the MAPK/ERK pathway's role in the CPM-mediated regulation of BMSC osteogenesis and adipogenesis; specifically, CPM overexpression enhanced MAPK/ERK signaling and osteogenesis. In contrast, the ERK1/2 inhibitor binimetinib negated the effects of CPM overexpression. Overall, our findings identify CPM as a pivotal regulator of BMSC differentiation, which provide new clues for the mechanistic study of OP.
2023-12-14 | GSE249471 | GEO
Project description:Periodontal ligament (PDL) stem-like cells (PDLSCs) are considered to be promising for the regeneration of periodontium because they demonstrate multipotency, high proliferative capacity, and potential to regenerate bone, cementum, and PDL tissue. However, the transplantation of autologous PDLSCs is restricted by limited availability and the need for tooth extraction to isolate these cells. PDLSCs are derived from neural crest cells (NCs) in early vertebrate development and NCs persist in adult PDL tissue. Therefore, we devised to promote the regeneration of periodontium by activating NCs to differentiate into PDLSCs and increasing their total number. SK-N-SH cells cultured on the extracellular matrix derived of human PDL cells (SK-PDLSCs) strongly expressed PDL-related marker genes and highly differentiated into mesenchymal lineage cells compared to untreated SK-N-SH cells. Expression levels of various hyaluronic acid (HA)-related genes were upregulated in induced pluripotent stem cells (iPSCs)-derived PDLSCs and SK-PDLSCs compared to iPSCs-derived NCs and SK-N-SH cells, respectively. Magnetic-activated cell sorting-assisted CD44-positive enrichment population of SK-N-SH cells showed higher expression of PDL-related marker genes after SK-PDLSCs induction than the CD44-negative population. Knockdown of CD44 in SK-N-SH cells significantly inhibited their ability to differentiate into SK-PDLSCs, while lower molecular HA (LHA) induction enhanced SK-PDLSC differentiation. LHA-containing electrospun nanofibrous membranes also promoted their SK-PDLSC differentiation. Our findings suggest that SK-N-SH cells are applied as a new model to induce the differentiation of NCs into PDLSCs. The LHA-CD44 relation is important for the differentiation of NCs into PDLSCs. LHA-containing electrospun nanofibrous membranes would promote the regeneration of periodontium by activating NCs in PDL tissue and increasing the total number of PDLSCs.
2023-06-27 | GSE235864 | GEO
Project description:The bone formation, osteogenesis, is a very complex process in which osteoblasts play a crucial role. The primary function of theses terminally differentiated mesenchymal stem cells is the secretion of fibrillary, dense, highly crosslinked type 1 collagen. Herein we show that the TENT5A gene, which mutations lead to osteogenesis imperfecta, is an active cytoplasmic poly(A) polymerase, which in osteoblast positively regulates the expression of collagen subunits and also other secreted proteins essential for proper bone formation. TENT5A substrates have shorter poly(A) tails in TENT5 KO, as revealed by direct RNA sequencing. In the case of Col1α1 and Col1α2 transcripts, the lack of cytoplasmic polyadenylation by TENT5 leads to drastic decree in the protein production but also aberrant structure. The increase in TENT5A expressing during osteoblasts differentiation positively correlates with the cytoplasmic extension of the poly(A) trials of mRNA targets. The first physiologically relevant regulation of collagen expression at the posttranscriptional level.
2022-02-16 | PXD020346 | Pride
Project description:<p> Skeletal healing requires the coordinated resolution of inflammation and precise lineage commitment of mesenchymal progenitors, yet the mechanisms coupling these processes remain incompletely defined. Here, we reveal that lymphatic vessels in bone serve as dynamic orchestrators bridging inflammatory clearance with stromal fate determination during regeneration. Using lineage tracing in Lyve1-creERT2; tdTomato mice and genetic ablation approaches, we demonstrate that injury-induced lymphangiogenesis is essential for timely osteogenesis. Prior depletion of lymphatic endothelial cells (LECs) exacerbates inflammation and impairs bone regeneration following injury. Notably, we identify Lyve1highmacrophages as lymphatic endothelial-like cells capable of transdifferentiation following efferocytosis. Mechanistically, engulfment of apoptotic cells activates fatty acid β-oxidation, increasing acetyl-CoA level that drive histone acetylation at the Lyve1 and Vegfc promoters, thereby licensing the macrophages-to-LECs transition. During the remodeling phase, lymphatic vessels help maintain local lipid homeostasis. Lymphatic impairment during bone repair leads to accumulation of polyunsaturated fatty acid-containing phosphatidylethanolamines (PE-PUFAs), which stabilize PPARγ through ZDHHC4-mediated palmitoylation. This process blocks ubiquitin-proteasome degradation and skews LepR+ bone mesenchymal stromal cells (BMSCs) toward adipogenesis at the expense of osteogenesis. Age-related lymphatic insufficiency recapitulates this pathological cascade, manifesting as impaired drainage, systemic lipid dysregulation, and compromised bone quality. Collectively, our findings establish lymphatic vessels, reconstructed by macrophages-to-LECs transdifferentiation, as stage-specific niche that guides osteogenic-adipogenic fate decision of BMSCs through lymphatic drainage capacity in skeletal repair.</p>
2026-01-17 | MTBLS13645 | MetaboLights