Resolving inflammation to promote stem cell-based bone regeneration
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE299815 | GEO | 2026/03/24
REPOSITORIES: GEO
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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:Intercellular mitochondrial transfer has recently been discovered as a strategy for local microenvironment regulation and repair. However, improving the efficiency of mitochondrial transfer and reducing immune rejection caused by implants is challenging for its application in bone regeneration tissue engineering. We found that bone marrow mesenchymal stem cells (BMSC)s can obtain mitochondria from macrophages through tunnel nanotubes (TNT)s. Mitochondria are crucial for the metabolism and function of BMSC. We further designed a composite hydrogel based on aldehyde sodium hyaluronate and chitosan as the network matrix, containing anti-inflammatory dimethyl itaconate (DMI) and macrophage-targeted zwitterionic nanoparticles (MDVNPs). The acidic bone injury microenvironment triggers a reversible Schiff base reaction in response to pH; further, the released DMI upregulates the M2 phenotype of macrophages by reducing the ROS level. Subsequently, MDVNPs with targeting, high transfection, and low immunogenicity accelerated the efficiency of mitochondrial transfer between macrophages and BMSC by increasing the expression of the mitochondrial transfer regulatory protein Rho GTPase 1 (Miro1). In vitro studies have confirmed that promoting mitochondrial transfer can effectively increase adenosine triphosphate (ATP) and oxidative phosphorylation (OXPHOS) levels in BMSC, promoting osteoblastic differentiation. In the mouse model of critical defect, the composite hydrogel (Gel@MDI) can reduce inflammatory reactions, improve energy metabolism, and enhance bone repair by promoting the balance between the immune system and bone metabolism. This study establishes a potential method for the immune microenvironment to enhance cellular mitochondrial bioenergy and achieve tissue regeneration by regulating mitochondrial transfer between cells.
2024-12-01 | GSE239590 | GEO
Project description:The objective of the present study was to compare the secretome of BMSC (BMSC-CM) to that of L-PRF (LPRF-CM) – an established standard for GF therapy, in the context of wound healing and regeneration.
2023-10-24 | PXD041617 | Pride
Project description:Loss or damage to the mandible due to trauma, treatment of oral malignancies, and other diseases is currently treated using bone grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to their mandibular bone, and thus offer an opportunity to understand how to boost intrinsic healing ability. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes. We also show that modulation of Notch signaling during the initial postoperative period results in lasting changes to regenerate bone quantity one month later. Notch signaling is required for mandibular bone healing, as pharmacological inhibition of Notch signaling blocks cartilage callus formation and results in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates regenerative ossification. Mechanistically, we report that postoperative Notch signaling regulates multiple phases of chondroid regeneration and patterns callus metabolic landscape. Given conserved functions of Notch signaling in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing may have therapeutic value.
2022-03-07 | PXD027280 | Pride
Project description:Objectives: Bone marrow mesenchymal stem cells (BMSC) play an important role in osteogenesis. However, the role of BMSC in osteopenia in spinal tuberculosis (STB) patients is unclear. Methods: Bone mineral density (BMD) of 53 STB patients and 55 controls was measured. The migration and osteogenesis of BMSC were assessed by wound healing assays and alizarin red staining, and osteoclast marker expression was measured. RNA-seq was performed on BMSC and the enriched signaling pathways were verified. Results:BMD of STB patients was significantly decreased and BMSC migration and osteogenesis were significantly reduced. After verification, we found that the B-cell receptor signaling pathway, tuberculosis, osteoclast differentiation, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were affected.And of these pathways, the B-cell receptor signaling, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were not previously known to be involved in osteopenia. The MAPK signaling pathway and ECM-receptor interactions were correlated with STB prognosis. Conclusion: STB infection can significantly reduce BMSC migration and osteogenesis, decreasing BMD. This process is regulated by multiple pathways and is associated with STB prognosis. Our study suggests that reduced BMSC migration and osteogenesis play important roles in osteopenia in STB patients, and BMSC may be a therapeutic target.
2023-12-01 | GSE222013 | GEO
Project description:Human bone marrow stromal cells (BMSCs) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key BMSC functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key BMSC regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSCs, downregulated upon culture, and lower in non-CFU-F-containing CD45neg BM cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSCs. Accordingly, EGR1 overexpression markedly decreased BMSC proliferation but considerably improved hematopoietic stroma support function as indicated by an increased production of transplantable CD34+CD90+ hematopoietic stem cells in expansion co-cultures. The improvement of BMSC stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. On the other hand, EGR1 knockdown increased ROS-mediated BMSC proliferation, and clearly reduced BMSC hematopoietic stroma support potential. These findings thus show that EGR1 is a key BMSC transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to coordinate the specific functions of BMSC in their different biological contexts.
2019-06-27 | PXD011767 | Pride
Project description:A functional vascular system is a prerequisite for bone repair as disturbed angiogenesis often causes non-union. Paracrine factors released from human bone marrow mesenchymal stromal cells (BMSCs) have angiogenic effects on endothelial cells. However, whether these paracrine factors participate in blood flow dynamics within bone capillaries remains poorly understood. Here, we used two different microfluidic designs to investigate critical steps during angiogenesis and found pronounced effects of endothelial cell proliferation as well as chemotactic and mechanotactic migration induced by BMSC conditioned medium (CM). The application of BMSC-CM in dynamic cultures demonstrates that bioactive factors in combination with fluidic flow-induced biomechanical signals significantly enhanced endothelial cell migration. Transcriptional analyses of endothelial cells demonstrate the induction of a unique gene expression profile related to tricarboxylic acid cycle and energy metabolism by the combination of BMSC-CM factors and shear stress, which opens an interesting new avenue to explore during fracture healing. Our results stress the importance of in vivo - like microenvironments simultaneously including biochemical, biomechanical and oxygen levels when investigating key events during vessel repair.
2023-01-01 | GSE208335 | GEO
Project description:Acomys exhibits a blunted immune response to wounding, and shares characteristics with fetal wound healing We used mouse microarrays to compare gene expression profiles during wound healing between the African spiny mouse (Acomys) and the house mouse (Mus)
2015-10-28 | E-GEOD-74387 | biostudies-arrayexpress
Project description:Bone fractures, the most common musculoskeletal injuries, heal through three main phases: inflammatory, repair, and remodeling. Around 10% of fracture patients suffer from impaired healing that requires surgical intervention, a huge burden on the healthcare system. The rate of impaired healing increases with metabolic diseases such as obesity-associated hyperglycemia/type 2 diabetes (T2D), an increasing concern given the growing incidence of obesity/T2D. Immune cells play pivotal roles in fracture healing, and obesity/T2D is associated with defective immune-cell functions. However, there is a gap in knowledge regarding the stoichiometry of immune cells that populate the callus and how that population changes during different phases of healing. Here, we used complementary global and single-cell techniques to characterize the repertoire of immune cells in the fracture callus and to identify populations specifically enriched in the fracture callus relative to the unfractured bone or bone marrow. Our analyses identified two clear waves of immune-cell infiltration into the callus: the first wave occurs during the early inflammatory phase of fracture healing, while the second takes place during the late repair/early remodeling phase. Innate immune cells were activated during the early inflammatory phase, but in later phases they returned to homeostatic numbers and activation levels. Of the innate immune cells, distinct subsets of activated dendritic cells were particularly enriched in the inflammatory healing hematoma. In contrast to innate cells, lymphocytes, including B and T cells, were enriched and activated in the callus primarily during the late repair phase. The Diet-Induced Obesity (DIO) mouse, an established model of obesity-associated hyperglycemia and insulin resistance, suffers from multiple healing defects. Our data demonstrate that DIO mice exhibit dysregulated innate immune responses during the inflammatory phase, and defects in all lymphocyte compartments during the late repair phase. Taken together, our data characterize, for the first time, immune populations that are enriched/activated in the callus during two distinct phases of fracture healing and identify defects in the healing-associated immune response in DIO mice, which will facilitate future development of immunomodulatory therapeutics for impaired fracture healing.
2023-09-01 | GSE240390 | GEO