Chromatin priming of skeletal stem progenitor cells governs cell fate during bone repair
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304752 | GEO | 2026/09/23
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.
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Project description:The development of alternatives for autologous bone grafts is a major focus of bone tissue engineering. To produce living implants, the use of skeletal stem and progenitor cells (SSPCs) are envisioned as key ingredients. SSPCs can be obtained from bone marrow, adipogenic tissue, dental pulp and periosteum. Human periosteum-derived cells (hPDCs) exhibit a number of progenitor characteristics and have well-documented in vivo bone formation capacity. Here, we have characterized and compared hPDCs derived from tibia with new sources of hPDCs, i.e. from maxilla and mandible (craniofacial hPDCs, as a potential source for tissue engineered implants for craniofacial applications.
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Project description:Bone regeneration involves skeletal stem/progenitor cells within periosteum and bone marrow, the formation of a fibrous callus followed by the deposition of cartilage and bone matrix to consolidate the fracture. Interactions between bone and skeletal muscle are known to play a role in bone repair but the underlying mechanisms are poorly understood. To better understand the role of skeletal muscle during bone repair, we characterized stem/progenitor cells within skeletal muscle that participate in bone repair. We show that cells originating from bone marrow, periosteum and skeletal muscle are all derived from the Prx1 embryonic lineage. We developed a mouse polytrauma model combining a non-stabilized tibial fracture and mechanical injury to adjacent skeletal muscles. In this polytrauma model, bone fracture healing is impaired. We characterized the Prx1-derived cell population within skeletal muscle in response to fracture and to polytrauma. To do so, we performed fracture and polytrauma in Prx1Cre;Rosa mTmG mice. We harvested skeletal muscle surrounding the tibia at d0 (uninjured), and surrounding the fracture site at d3 and d5 post-fracture or post-polytrauma. Following enzymatic and mechanical digestion of skeletal muscle tissue, we FACS sorted Prx1-derived GFP+ cells and sequenced them using the 10X Chromium technology.
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Project description:Distinct skeletal stem/progenitor cells (SSPCs) have been identified in the bone marrow, growth plate, and periosteum, which are indispensable for the maintenance and remodeling of the adult skeleton. However, the decline of which cell types are responsible for age-related bone loss and what characteristic changes of these cells during aging remain to be determined. Here, we constructed premature skeletal aging models by depleting metalloproteinase Zmpste24 (Z24) in mice and found that Prx1-dependent, but not Osx-dependent, Z24 deletion caused significant bone loss. Single-cell RNA sequencing (scRNA-seq) revealed that Prx1-expressing cells in the periosteum (pSSPCs) and growth plate (gpSSPCs) significantly declined in progeria mice. Consistent with aggrecan (Acan) expression in gpSSPCs but not pSSPCs, Acan-linked Z24 depletion only caused trabecular bone loss. Chromatin and transcriptional profiling demonstrate that premature aged SSPCs gain apoptotic signaling pathway and mechanosensation decline. Moreover, SSPCs increased after physical exersice and Z24 depletion’s effects on cellular apoptosis and extracellular matrix expression were reverted by mechanical stimuli. Overall, this study identifies that Z24 deficiency-induced impairment of mechanosensation in SSPCs causes bone loss, shedding new insight on how physical exercise can be used to improve bone quality and prevent bone aging.
2023-08-01 | GSE207240 | GEO
Project description:Bone regeneration relies on the activation of skeletal stem cells (SSCs) that still remain poorly characterized. Here, we show that periosteum contains SSCs with high bone regenerative potential compared to bone marrow stromal cells/skeletal stem cells (BMSCs) in mice. Although periosteal cells (PCs) and BMSCs are derived from a common embryonic mesenchymal lineage, post-natally PCs exhibit greater clonogenicity, growth and differentiation capacity than BMSCs. During bone repair, PCs can efficiently contribute to cartilage and bone, and integrate long-term after transplantation. Molecular profiling uncovers genes encoding Periostin and other extracellular matrix molecules associated with the enhanced response to injury of PCs. Periostin gene deletion impairs PC functions and fracture consolidation. Periostin-deficient periosteum cannot reconstitute a pool of PCs after injury demonstrating the presence of SSCs within periosteum and the requirement of Periostin in maintaining this pool. Overall our results highlight the importance of analyzing periosteum and PCs to understand bone phenotypes.
2018-10-18 | E-MTAB-6417 | biostudies-arrayexpress
Project description:We present a transcriptomic analysis that provides a better understanding of regulatory mechanisms within the healthy and injured periosteum leading to novel translational approaches for bone healing. The focus of this work is on the early regulatory control of bone healing by completing a transcriptomic analysis of forming periosteal callus cells on day 3 post fracture. Based on our previous work indicating that induced Notch1 signaling in osteoprogenitors leads to better healing, we contrasted samples in which Notch 1 intracellular domain (NICD1) is overexpressed by periosteal stem/progenitor cells with control unperturbed periosteum. We determined molecular mechanisms and changes in skeletal stem/progenitor cells (SSPC) and other cell populations within callus including hematopoietic lineages. Notch ligands were differentially expressed in endothelial and mesenchymal populations, with Dll4 restricted to endothelial cells while Jag1 expressed by various mesenchymal populations. When targeting deletion of Dll4 in SSPCs using a-smooth muscle actin (aSMACreER) in mesenchymal cells there was no phenotype, while deletion in EC using Cdh5CreER exhibited negative effects on the early fracture healing. Translation of these observations into clinically relevant model of bone healing revealed the positive effects of combination of Notch ligands delivery with currently used osteogenic inducer BMP2.
2025-03-01 | GSE260749 | GEO
Project description:The phases of fracture healing have been well characterized. However, the exact source and genetic profile of the skeletal progenitors that participate in bone repair is somewhat unclear. Sox9 expression in skeletal elements precedes bone and cartilage formation and a Sox9+ cell type is retained in the adult periosteum. We hypothesized that Sox9+ periosteal cells are multipotent skeletal progenitors normally participating in fracture repair. To test this hypothesis we used tamoxifen (TM)-mediated lineage tracing of Sox9+ cells in Sox9CreErt2:Td-Tomato mice. TM injection indelibly labels Sox9+ cells and all their descendants with the fluorescent reporter protein Td-Tomato. Intact mouse femora were harvested 2 weeks after TM injection and analyzed by histology and immunostaining and RNA sequencing, to evaluate the skeletal distribution and gene expression profile of Td-Tomato positive cells in the adult femur. To assess the role of these cells in fracture repair, mice underwent a closed mid-diaphyseal femoral fracture and their hind limbs were harvested at 3, 9 or 56 days post-fracture to assess the contribution of Sox9+ and Td-tomato+ cells in the fracture healing process. In the intact adult mouse femur, Td-Tomato-labelled cells were observed in articular and growth plate cartilage where Sox9 is known to be expressed, but also in the primary spongiosa, periosteum, and endosteum. RNA sequencing and subsequent analysis showed that Td-Tomato positive periosteal cells were enriched in Sox9 transcripts, and transcripts for various osteogenic and chondrocyte specific genes. In a femoral fracture model, we showed that pre-labeled Td-Tomato positive descendent cells were mobilized during the fracture repair process, expanding and migrating towards the fracture site 3 days post-fracture. Here, Td-Tomato positive cells differentiate into chondrocytes and osteoblasts in the soft and hard callus, respectively, 9 days post-fracture. By 2 months post-fracture, descendants of the original Sox9 labelled cell population were prevalent in the cortex and periosteum, and amongst the differentiated osteocyte population embedded within the cortical bone. Thus, a Sox9+ progenitor population resides in the adult periosteum. Fate tracing shows that these cells likely play a substantial role in repair of the fractured femur giving rise to chondrocytes, osteoblasts and mature cortical osteocytes. To our knowledge this is the first report of this Sox9+ cell population in the periosteum of the adult long bone. Taken together with developmental studies on skeletal formation, our data suggest that Sox9+ osteochondroprogenitors play a continuous role in skeletal formation throughout life.
2018-04-25 | GSE98587 | GEO
Project description:Bone fracture healing requires skeletal stem cells (SSCs), which facilitate intramembranous ossification and endochondral ossification in long bone fractures. Although the periosteum is necessary for bone homeostasis and regeneration, the in vivo origin and regulatory mechanisms of periosteal SSCs (P-SSCs) remain unclear. Here, we identified Postn+ P-SSCs at the cambium layer of the periosteum that actively orchestrate regeneration in response to bone injury. Notably, the Postn+ P-SSCs that arise during bicortical fractures are likely derived from Gli1+ P-SSCs. In addition, Postn+ cell ablation compromises cortical bone homeostasis and bone regeneration. The IGF signal is indispensable in the regulatory effect of Postn+ P-SSCs on bicortical fractures since the genetic deletion of Igf1r in Postn+ cells dampens bone fracture healing. Taken together, adult Postn+ cells are region-specific P-SSCs that contribute to bone homeostasis and regeneration and are partially dependent upon IGF signaling.
2024-10-16 | GSE255137 | GEO