Correction to: Partial Tendon Injury at the Tendon-to-Bone Enthesis Activates Skeletal Stem Cells.
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PROVIDER: S-EPMC9397648 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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Correction to: Partial Tendon Injury at the Tendon-to-Bone Enthesis Activates Skeletal Stem Cells.
Stem cells translational medicine 20220801 8
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Project description:The tendon enthesis plays a critical role in facilitating movement and reducing stress within joints. Partial enthesis injuries heal in a mechanically inferior manner and never achieve healthy tissue function. The cells responsible for tendon-to-bone healing remain incompletely characterized and their origin is unknown. Here, we evaluated the putative role of mouse skeletal stem cells (mSSCs) in the enthesis after partial-injury. We found that mSSCs were present at elevated levels within the enthesis following injury and that these cells downregulated TGFβ signaling pathway elements at both the RNA and protein levels. Exogenous application of TGFβ post-injury led to a reduced mSSC response and impaired healing, whereas treatment with a TGFβ inhibitor (SB43154) resulted in a more robust mSSC response. Collectively, these data suggest that mSSCs may augment tendon-to-bone healing by dampening the effects of TGFβ signaling within the mSSC niche.
| S-EPMC9299518 | biostudies-literature
Project description:Partial tendon-to-bone interface (TBI) injuries heal in a mechanically inferior manner and redevelop healthy uninjured tissue morphology. The origin of the cells involved in tendon-to-bone healing remains unknown. We employed a rigorous approach to evaluate if mouse skeletal stem cells (mSSC) play a role in tendon-to-bone healing after partial-injury. Using fluorescence-activated cell sorting we identified that found that they are present within the TBI. Using a TBI-injury rainbow lineage tracing mouse model, we demonstrated that injury-responsive cells within the TBI and calcaneus proliferate polyclonally following partial-tendon injury at the TBI. These injury-responsive clonal cells express skeletal marker SP7. We quantified the differences in mSCC frequency after TBI-injury and found that mSSC respond to injury with a higher frequency and have associated changes in gene expression, with the specific down-regulation of the TGFβ signaling pathway. Exogenous delivery of TGFβ after injury was found to reduce the mSSC response after injury. These findings suggest that mSSC may facilitate tendon-to-bone healing by downregulating TGFβ signaling within the mSSC niche.
2022-02-14 | GSE167080 | GEO
Project description:Partial Tendon Injury at the Tendon-to-Bone Enthesis Activates Skeletal Stem Cells
| PRJNA719822 | ENA
Project description:BackgroundBone marrow mesenchymal stem cells (BMSCs) have immense potential in applications for the enhancement of tendon-bone (T-B) healing. Recently, it has been well-reported that skeletal stem cells (SSCs) could induce bone and cartilage regeneration. Therefore, SSCs represent a promising choice for cell-based therapies to improve T-B healing. In this study, we aimed to compare the therapeutic potential of SSCs and BMSCs for tendon-bone healing.MethodsSSCs and BMSCs were isolated by flow cytometry, and their proliferation ability was measured by CCK-8 assay. The osteogenic, chondrogenic, and adipogenic gene expression in cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). C57BL/6 mice underwent unilateral supraspinatus tendon detachment and repair, and the mice were then randomly allocated to 4 groups: control group (tendon-bone interface without any treatment), hydrogel group (administration of blank hydrogel into the tendon-bone interface), hydrogel + BMSCs group (administration of hydrogel with BMSCs into the tendon-bone interface), and hydrogel + SSCs group (administration of hydrogel with SSCs into the tendon-bone interface). Histological staining, Micro-computed tomography (Micro-CT) scanning, biomechanical testing, and qRT-PCR were performed to assay T-B healing at 4 and 8 weeks after surgery.ResultsSSCs showed more cell proportion, exhibited stronger multiplication capacity, and expressed higher osteogenic and chondrogenic markers and lower adipogenic markers than BMSCs. In vivo assay, the SSCs group showed a better-maturated interface which was characterized by richer chondrocytes and more proteoglycan deposition, as well as more newly formed bone at the healing site and increased mechanical properties when compared to other there groups. qRT-PCR analysis revealed that the healing interface in the SSCs group expressed more transcription factors essential for osteogenesis and chondrogenesis than the interfaces in the other groups.ConclusionsOverall, the results demonstrated the superior therapeutic potential of SSCs over BMSCs in tendon-bone healing.The translational potential of this articleThis current study provides valuable insights that SSCs may be a more effective cell therapy for enhancing T-B healing compared to BMSCs.
| S-EPMC11245954 | biostudies-literature
Project description:Several features of the tendon-to-bone attachment were examined allometrically to determine load transfer mechanisms. The humeral head diameter increased geometrically with animal mass. Area of the attachment site exhibited a near isometric increase with muscle physiological cross section. In contrast, the interfacial roughness as well as the mineral gradient width demonstrated a hypoallometric relationship with physiologic cross-sectional area (PCSA). The isometric increase in attachment area indicates that as muscle forces increase, the attachment area increases accordingly, thus maintaining a constant interfacial stress. Due to the presence of constant stresses at the attachment, the micrometer-scale features may not need to vary with increasing load.
| S-EPMC5024979 | biostudies-literature
Project description:Large joints are composed of two closely linked cartilages: articular cartilage (AC; rich in type II collagen, a well-studied tissue) and fibrocartilaginous enthesis (FE; rich in type I collagen, common disorder sites of enthesopathy and sporting injuries, although receiving little attention). For many years, both cartilages were thought to be formed by chondrocytes, whereas tendon, which attaches to the humeral bone head, is primarily considered as a completely different connective tissue. In this study, we raised an unconventional hypothesis: tendon cells directly form FE via cell transdifferentiation. To test this hypothesis, we first qualitatively and quantitatively demonstrated distinct differences between AC and FE in cell morphology and cell distribution, mineralization status, extracellular matrix (ECM) contents, and critical ECM protein expression profiles using comprehensive approaches. Next, we traced the cell fate of tendon cells using ScxLin (a tendon specific Cre ScxCreERT2; R26R-tdTomato line) with one-time tamoxifen induction at early (P3) or young adult (P28) stages and harvested mice at different development ages, respectively. Our early tracing data revealed different growth events in tendon and FE: an initial increase but gradual decrease in the ScxLin tendon cells and a continuous expansion in the ScxLin FE cells. The young adult tracing data demonstrated continuous recruitment of ScxLin cells into FE expansion during P28 and P56. A separate tracing line, 3.2 Col 1Lin (a so-called "bone-specific" line), further confirmed the direct contribution of tendon cells for FE cell formation, which occurred in days but FE ECM maturation (including high levels of SOST, a potent Wnt signaling inhibitor) took weeks. Finally, loss of function data using diphtheria toxin fragment A (DTA) in ScxLin cells demonstrated a significant reduction of ScxLin cells in both tendons and FE cells, whereas the gain of function study (by stabilizing β-catenin in ScxLin tendon cells via one-time injection of tamoxifen at P3 and harvesting at P60) displayed great expansion of both ScxLin tendon and FE mass. Together, our studies demonstrated that fibrocartilage is an invaded enthesis likely originating from the tendon via a quick cell transdifferentiation mechanism with a lengthy ECM maturation process. The postnatally formed fibrocartilage roots into existing cartilage and firmly connects tendon and bone instead of acting as a simple attachment site as widely believed. We believe that this study will stimulate more intense exploring in this understudied area, especially for patients with enthesopathy and sporting injuries.
| S-EPMC9760439 | biostudies-literature
Project description:On May 22, 2017, the National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) hosted a roundtable on "Innovative Treatments for Enthesis Repair." A summary of the roundtable discussion, as well as a list of the extramural participants, can be found at https://www.niams.nih.gov/about/meetings-events/roundtables/roundtable-innovative-treatments-enthesis-repair. This paper reviews the challenges and opportunities for developing effective treatment strategies for enthesis repair that were identified at the roundtable discussion.
| S-EPMC6133216 | biostudies-literature
Project description: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).
| S-EPMC9543664 | biostudies-literature
Project description:RationaleThe mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood.ObjectiveTo test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells.Methods and resultsSerial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (P<0.05 versus pre tMCAO). Flow cytometry and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19% to 7.32%±0.52% after tMCAO (P<0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system's myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (P<0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose (P<0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the β3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, P=0.51).ConclusionsIschemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6C(high) monocytes and neutrophils.
| S-EPMC4312511 | biostudies-literature
Project description:Our studies used scRNA-seq analysis to get a full map of transcriptional profiles of enthesis cells and also a seprate Gli1-lineage enthesis stem cells. By harvesting enthesis cells from different development stages for scRNA-seq analysis, we revealed enthesis cell heterogeneity and identified six cell sub-populations using scRNA-seq. We infered cell differentiation trajectories for enthesis stem cells differentiating into mineralizing chondrocytes. A gene regulatory network analysis combined fluorescent in situ hybridization were then used to identify a number of transcription factors coordinating tenogenesis, chondrogenesis, and osteogenesis to form an enthesis with spatially graded mineralization.To further define the enthesis stem cell population, enthesis Gli1-lineage cells were isolated and their transcriptomes were characterized at single cell resolution. These specific Gli1-responsive cells had a linear trajectory and a capacity of chondrogenesis and osteogenesis. The full characterization of transcriptional landscape of tendon enthesis stem cells demonstrates a promising therapeutic strategies using this cell source for enthesis regeneration.
2022-12-01 | GSE182997 | GEO