Single nuclei RNAseq of the periosteal response to bone fracture and musculoskeletal traumatic injury in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE268276 | GEO | 2024/10/22
REPOSITORIES: GEO
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Project description:Bone regeneration is a highly efficient process allowing scarless healing after injury. The periosteum, the outer layer of bones, is a critical source of skeletal stem/progenitor cells (SSPCs), as well as immune, endothelial and neural cells during bone repair. In our study, we generated a single-nuclei atlas of the murine periosteal response to bone fracture. We generated single nuclei datasets from uninjured periosteum and from injured periosteum and hematoma/fracture callus at days 5 and 7 post-injury from wild-type mice.
2024-04-01 | GSE234451 | GEO
Project description:The fracture hematoma that forms between the broken fragments of bone serves as a natural fibrin scaffold. However, there is no data regarding the differences between the micro-architectural and biological properties of hematomas formed in normally healing, delayed healing, and non-healing bone defects. Mimicking these three conditions in the rat femur, we demonstrate clear differences in fibrin clot morphology, which directly affect the gene expression pattern. Specifically, RNA-sequencing reveals that the expression of essential osteogenic genes in normally healing defects are significantly up-regulated, whereas in delayed and non-healing defects they are down-regulated. Surprisingly, there were no substantial differences between delayed and non-healing defects. Most importantly, this study demonstrates that the healing outcome has already been determined at the earliest stage of bone healing. These findings could be used to develop biomaterial scaffolds mimicking the micro-architectural properties of normally healing fracture hematoma as a treatment strategy for bone defects. The hypothesis of this study was that the micro-architectural properties of the initially formed hematoma has a significant effect on the regulation of the biological process at the fracture site, which ultimately determines the outcome of bone healing. Three different healing models were investigated - normally healing, delayed healing, and non-healing defects. The results demonstrated that the intrinsic micro-architectural properties of hematomas between those groups varied distinctly in terms of fiber diameter, porosity, and density of the formed fibrin network. Those differences influenced biological responses, as evidenced by a higher expression of osteogenic genes in normally healing compared to delayed and non-healing defects, and the failed activation of BMP-2 in non-healing defects. More importantly, our results demonstrate healing outcomes are already determined at the initial (hematoma) stage of bone healing.
2023-11-01 | GSE161315 | GEO
Project description:Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system plays a pivotal role in regulating immune system and skeleton, however, the impact of TBI on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. Importantly, the adrenergic hypersensitivity swiftly skews bone marrow hematopoietic lineage cells toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptors (ARs) eliminate TBI mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. Moreover, β3- and β2-ARs agonists synergistically promote M2 macrophages infiltration in callus and accelerate bone healing process. Our results suggest that TBI shapes the anti-inflammation environment during early stage of fracture healing, implicating the sympathetic nerve system as a potential target that can be exploited to treat fracture.
2023-04-12 | GSE229258 | GEO
Project description:Lymphatic vessels (LVs) interdigitated with blood vessels, travel and form an extensive transport network in the musculoskeletal system. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, by near infrared indocyanine green lymphatic imaging (NIR-ICG), we examined lymphatic drainage function at the tibial fracture sites and found lymphatic drainage insufficiency (LDI) occurred as early as two weeks after fracture. Sufficient lymphatic drainage facilitates fracture healing. In addition, we identified that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, caused LDI and then inhibited fracture healing, which can be rescued by a pharmacological approach. Moreover, unblocked lymphatic drainage inhibits neutrophils influx and induce M2-like macrophages palarization of hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs). These findings demonstrate that LPT limits fracture healing by blocking lymphatic drainage from transporting DAMPs. Together, these findings represent a novel way forward in the treatment of bone fracture healing.
2023-08-28 | PXD044917 |
Project description:Traumatic lower-limb musculoskeletal injuries are pervasive amongst athletes and the military and typically an individual returns to activity prior to fully healing, increasing a predisposition for additional injuries and chronic pain. Monitoring healing progression after a musculoskeletal injury typically involves different types of imaging but these approaches suffer from several disadvantages. Isolating and profiling transcripts from the injured site would abrogate these shortcomings and provide enumerative insights into the regenerative potential of an individual’s muscle after injury. In this study, a traumatic injury was administered to a mouse model and healing progression was examined from 3 hours to 1 month using high-throughput RNA-Sequencing (RNA-Seq). Comprehensive dissection of the genome-wide datasets revealed the injured site to be a dynamic, heterogeneous environment composed of multiple cell types and thousands of genes undergoing significant expression changes in highly regulated networks. Four independent approaches were used to determine the set of genes, isoforms, and genetic pathways most characteristic of different time points post-injury and two novel approaches were developed to classify injured tissues at different time points. These results highlight the possibility to quantitatively track healing progression in situ via transcript profiling using high- throughput sequencing.
2017-07-26 | GSE101900 | GEO
Project description:In the musculoskeletal system, lymphatic vessels (LVs), which are interdigitated with blood vessels, travel and form an extensive transport network. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, we investigated the lymphatic draining function at the tibial fracture sites using near-infrared indocyanine green lymphatic imaging (NIR-ICG) and discovered that lymphatic drainage insufficiency (LDI) started on day one and persisted for up to two weeks following the fracture. Sufficient lymphatic drainage facilitates fracture healing. Furthermore, we identified that lymphatic platelet thrombosis (LPT) blocked the draining lymphoid sinus and LVs, caused LDI, and then inhibited fracture healing, which can be rescued by a pharmacological approach. Moreover, unblocked lymphatic drainage decreased neutrophils and increased M2-like macrophages of the hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs). Lymphatic platelet thrombolysis also benefits senile fracture healing. These findings demonstrate that LPT limits bone regeneration by impeding lymphatic transporting DAMPs. Together, these findings represent a novel way forward in the treatment of bone repair.
2024-10-05 | PXD056584 |
Project description:Aberrant repair after musculoskeletal injury is one of the most costly and common clinical scenarios in health care. While advances in our understanding of the key cells and pathways during the repair process have improved, there remains a gap in knowledge of the key progenitor cells and their interaction with the surrounding microenvironment. Heterotopic ossification (HO) is a pathological process caused by aberrant cell-fate determination resulting in the formation of bone in non-skeletal tissues after musculoskeletal injury. While the involvement of blood vessels in musculoskeletal repair is well-documented, the role of lymphatic vessels and the cells responsible for their ingrowth in musculoskeletal tissues during both homeostasis and after injury remains poorly understood. In this study, we employed a mouse model of traumatic HO to investigate lymphangiogenesis during musculoskeletal injury and repair and to uncover the key progenitor cells responsible to stimulate lymphangiogenesis and undergo aberrant cell fate differentiation. Our findings demonstrated that musculoskeletal injury triggered lymphangiogenesis at the injury site, including invasion of lymphatic vessels into the tendon proper. This increased lymphangiogenesis was driven by elevated levels of active Vascular Endothelial Growth Factor C (VEGF-C) one-week post-injury. Through single-cell transcriptomic analyses, we identified mesenchymal progenitor cells (MPCs) as a source of Vegfc following injury as well as the source of enzymes responsible for activating VEGF-C. These Vegfc-expressing MPCs underwent osteochondral differentiation and actively contributed to the formation of HO following injury. Notably, Vegfc haploinsufficiency resulted in a near 50% reduction in lymphangiogenesis and HO formation. Collectively, these findings suggest that MPC expression of VEGF-C and its activating enzymes in response to soft tissue trauma play a critical role in stimulating pathologic lymphatic vessel growth. Furthermore, Vegfc expressing MPCs undergo aberrant osteochondral differentiation responsible for HO. Targeting Vegfc expression and Vegfc-expressing progenitors therapeutically could potentially mitigate pathologic lymphangiogenesis, preventing aberrant tissue repair and subsequent HO formation.
2024-06-13 | GSE255500 | GEO
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
Project description:Periosteum is a major source of skeletal stem/progenitor cells (SSPCs) during bone repair. However, the cellular composition of the periosteum is poorly characterized. Here, we provide single-cell RNAseq data of periosteal cells isolated by explant culture at steady state and at day 3 post-tibial fracture. We found that periosteal cell populations are heterogeneous containing several sub-populations of SSPCs. Upon fracture, SSPCs are activated by leaving their mesenchymal state, and engaging into fibrogenesis prior to chondrogenesis.
2022-08-10 | GSE195940 | GEO
Project description:Background: Due to their excellent mechanical and biocompatibility properties, titanium-based implants are successfully used as biomedical devices. However, when new bone formation fails for different reasons, impaired fracture healing will become a clinical problem and will affect the patient's quality of life. This study proposes to design a new bioactive surface of titanium implants with a synergetic PEG biopolymer-based composition for gradual delivery of growth factors (FGF2, VEGF, and BMP4) during bone healing. Methods: The optimal architecture of non-cytotoxic polymeric coatings deposited by dip coating under controlled parameters was assessed both in cultured cells and on rat in vivo animal model (100% viability). Results: Notably, the titanium adsorbed polymer matrix induced an improved healing process when compared with the individual action of each biomolecules. High-performance mass spectrometry analysis demonstrated that recovery after a traumatic event is governed by specific differentially regulated proteins, acting in a coordinated response to the external stimulus. Predicted protein interactions shown by STRING analysis were well organized in hub-based networks related with response to chemical, wound healing and response to stress pathways. Conclusions: The described functional polymer coatings of the titanium implants demonstrated the significant improvement of bone healing process after injury.
2021-04-29 | PXD016135 | Pride