Heterogeneity of murine periosteum progenitors involved in fracture healing

Matthews, Brya G.; Novak, Sanja; Sbrana, Francesca; Funnell, Jessica L; Cao, Ye; Buckels, Emma J.; Grčević, Danka; Kalajzić, Ivo

doi:10.1101/2020.06.24.169003

Cited by 9 publications

(19 citation statements)

References 76 publications

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“…(1)(2)(3)(4)(5)(6)(7)(8)(9)(10) These SSPC populations are diverse in their tissue origin and in their cellular composition, as revealed by single-cell RNAseq (scRNAseq). (2,(11)(12)(13)(14)(15)(16) Multiple markers have been used to identify SSPCs in bone marrow (ie, Mx1, Grem1, LepR, Nes, Cxcl12, Pdgfra, Gli1) or in periosteum (ie, Ctsk, Acta2), (12,(17)(18)(19)(20)(21)(22)(23) but none of these markers is restricted to a single tissue. (11)(12)(13)(14)(15)(16)(17)(18) Despite the cellular diversity of SSPCs, functional analyses in adult tissues indicate unique regenerative potential of SSPCs according to their origin.…”

Section: Introductionmentioning

confidence: 99%

“…( 1‐10 ) These SSPC populations are diverse in their tissue origin and in their cellular composition, as revealed by single‐cell RNAseq (scRNAseq). ( 2,11‐16 ) Multiple markers have been used to identify SSPCs in bone marrow (ie, Mx1 , Grem1 , LepR , Nes , Cxcl12 , Pdgfra , Gli1 ) or in periosteum (ie, Ctsk , Acta2 ), ( 12,17‐23 ) but none of these markers is restricted to a single tissue. ( 11‐18 )…”

Section: Introductionmentioning

confidence: 99%

“…(2,(11)(12)(13)(14)(15)(16) Multiple markers have been used to identify SSPCs in bone marrow (ie, Mx1, Grem1, LepR, Nes, Cxcl12, Pdgfra, Gli1) or in periosteum (ie, Ctsk, Acta2), (12,(17)(18)(19)(20)(21)(22)(23) but none of these markers is restricted to a single tissue. (11)(12)(13)(14)(15)(16)(17)(18) Despite the cellular diversity of SSPCs, functional analyses in adult tissues indicate unique regenerative potential of SSPCs according to their origin. Bone marrow SSPCs are osteogenic, support hematopoiesis and osteoclast formation, play paracrine and immunomodulatory roles, but show limited capacity to form cartilage during bone repair (19,24,25) .…”

Section: Introductionmentioning

confidence: 99%

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Skeletal Stem/Progenitor Cells in Periosteum and Skeletal Muscle Share a Common Molecular Response to Bone Injury

Julien

Perrin

Martínez‐Sarrà

et al. 2020

Journal of Bone and Mineral Research

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Bone regeneration involves skeletal stem/progenitor cells (SSPCs) recruited from bone marrow, periosteum, and adjacent skeletal muscle. To achieve bone reconstitution after injury, a coordinated cellular and molecular response is required from these cell populations. Here, we show that SSPCs from periosteum and skeletal muscle are enriched in osteochondral progenitors, and more efficiently contribute to endochondral ossification during fracture repair as compared to bone‐marrow stromal cells. Single‐cell RNA sequencing (RNAseq) analyses of periosteal cells reveal the cellular heterogeneity of periosteum at steady state and in response to bone fracture. Upon fracture, both periosteal and skeletal muscle SSPCs transition from a stem/progenitor to a fibrogenic state prior to chondrogenesis. This common activation pattern in periosteum and skeletal muscle SSPCs is mediated by bone morphogenetic protein (BMP) signaling. Functionally, Bmpr1a gene inactivation in platelet‐derived growth factor receptor alpha (Pdgfra)‐derived SSPCs impairs bone healing and decreases SSPC proliferation, migration, and osteochondral differentiation. These results uncover a coordinated molecular program driving SSPC activation in periosteum and skeletal muscle toward endochondral ossification during bone regeneration. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Skeletal Stem/Progenitor Cells in Periosteum and Skeletal Muscle Share a Common Molecular Response to Bone Injury

Julien

Perrin

Martínez‐Sarrà

et al. 2020

Journal of Bone and Mineral Research

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“…To assess the injury-associated emergence of Prg4 hi Rspo2-expressing lining SFs, we performed trajectory analysis within the SF niche using Monocle3. This analysis identified Dpp4+ progenitors as precursors for Prg4 hi lining SFs across pseudotime, via an αSMA+ intermediate akin to that seen in other musculoskeletal injury models such as fracture healing(36, 37) (Figure 4I and Figure S8H). This differentiation was supported by pseudotime regression analysis of genes unique to the Dpp4+ root ( Dpp4, Pi16, Wnt2 ) or the Prg4 hi terminus ( Prg4, Col22a1, Rspo2 ) of the proposed trajectory (Figure 4J-K).…”

Section: Resultsmentioning

confidence: 71%

Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Knights

Farrell

Ellis

et al. 2022

Preprint

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ObjectivesSynovium is acutely affected following joint trauma and contributes to post-traumatic osteoarthritis (PTOA) progression. Little is known about discrete cell types and molecular mechanisms in PTOA synovium. We aimed to describe synovial cell populations and their dynamics in PTOA, with a focus on fibroblasts. We also sought to define mechanisms of synovial Wnt/β-catenin signaling, given its emerging importance in arthritis.MethodsWe subjected mice to non-invasive anterior cruciate ligament rupture as a model of human joint injury. We performed single-cell RNA-sequencing to assess synovial cell populations, subjected Wnt-GFP reporter mice to joint injury to study Wnt-active cells, and performed intra-articular injections of the Wnt agonist R-spondin 2 (Rspo2) to assess whether gain-of-function induced pathologies characteristic of PTOA. Lastly, we used cultured fibroblasts, macrophages, and chondrocytes to study how Rspo2 orchestrates crosstalk between joint cell types.ResultsWe uncovered seven distinct functional subsets of synovial fibroblasts in healthy and injured synovium, and defined their temporal dynamics in early and established PTOA. Wnt/β-catenin signaling was overactive in PTOA synovium, and Rspo2 was strongly induced after injury and secreted exclusively by Prg4hi lining fibroblasts. Trajectory analyses predicted that Prg4hi lining fibroblasts arise from a pool of Dpp4+ mesenchymal progenitors in synovium, with SOX5 identified as a potential regulator of this emergence. We also showed that Rspo2 orchestrated pathological crosstalk between synovial fibroblasts, macrophages, and chondrocytes.ConclusionsSynovial fibroblasts assume distinct functional identities during PTOA, and Prg4hi lining fibroblasts secrete the Wnt agonist Rspo2 to drive pathological crosstalk in the joint after injury.

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“…These findings indicate that there are temporally and spatially restricted resident cell populations that reside in different skeletal tissues (Yamaza et al 2011). The periosteum is the major source of stem cells and progenitor cells involved in skeletal development and defect healing (Matthews et al 2021). To date, how the periosteal osteogenic progenitor population contributes to jawbone remodeling and healing remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Identification of Periosteal Osteogenic Progenitors in Jawbone

Ding

Geng

et al. 2022

J Dent Res

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Unlike long bones, jawbone development is mainly accomplished by intramembranous ossification resulting from the differentiation of periosteal progenitor cells. However, the spatiotemporal ontogeny of periosteal progenitor cells during jawbone development and repair remains elusive. In this study, we mapped the transcriptional landscape of the human jawbone periosteum at single-cell resolution and identified a cathepsin K (Ctsk)+ periosteal subset. Lineage tracing analysis indicated that Ctsk-Cre–labeled periosteal cells could make contributions to jawbone development. However, different from the periosteal-specific location of Ctsk+ cells in long bone, we also identified Ctsk+ stromal cells in jawbone marrow and implied the heterogeneity of jawbone Ctsk+ hierarchy. In further analysis of the periosteal progenitor cell subset of heterogeneous Ctsk+ hierarchy, we identified a unique Ctsk+Ly6a+ subset of cells. The additional marker Ly6a helped to further confine the progenitor subset to the jawbone periosteum and was nearly undetectable in the bone marrow. Defects in the jawbone could activate the migration and osteogenic differentiation of Ctsk+Ly6a+ cells. Local ablation of Ctsk+ cells by diphtheria reduced the number of Ctsk+Ly6a+ cells and delayed the repair of the bone defect. Taken together, we identify a novel periosteal osteogenic progenitor subset that is active in jawbone osteogenesis and healing.

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Heterogeneity of murine periosteum progenitors involved in fracture healing

Cited by 9 publications

References 76 publications

Skeletal Stem/Progenitor Cells in Periosteum and Skeletal Muscle Share a Common Molecular Response to Bone Injury

Skeletal Stem/Progenitor Cells in Periosteum and Skeletal Muscle Share a Common Molecular Response to Bone Injury

Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Identification of Periosteal Osteogenic Progenitors in Jawbone

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