GNAS/PKA pathway promotes aberrant osteochondral differentiation of Gli1+ tendon sheath progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298748 | GEO | 2025/07/28
REPOSITORIES: GEO
Similar Datasets
Project description:GNAS/PKA pathway promotes aberrant osteochondral differentiation of Gli1+ tendon sheath progenitors
| PRJNA1271048 | ENA
Project description:Heterotopic ossification (HO), usually following traumatic challenges, is initiated by the aberrant osteochondral differentiation of mesenchymal stem cell (MSC). However, the role of trauma-induced inflammatory exposure in MSC fate determination remains unclear. Here, we found that quiescent MSC transited into cycling MSC and later gave rise to chondrogenic (cMSC) and/or osteogenic (oMSC) commitment following either muscle or tendon injury via single-cell RNA sequencing and lineage tracing analysis. Further spatial transcriptome analysis revealed that cycling MSC, cMSC and oMSC resided in the inflammatory niche comprised of monocytes/macrophages, neutrophils, dendritic cells (DCs), NK cells, T and B lymphocytes. We uncovered the diversity of each type of immune cells during MSC development and demonstrated that macrophages, including M1 and M2 subtypes, dynamically promotes proliferation and osteochondral differentiation of MSCs. Additionally, neutrophils and NK cells are essential for cycling MSC transition from quiescent MSC. CD4+ and CD8+ T lymphocytes promotes chondrogenesis. CellchatDB analysis and regulon analysis identify several gene networks, which could be essential for aberrant MSC proliferation and osteochondral differentiation respectively. Collectively, our findings indicate that inflammation is necessary to regulate MSC fate and uncovered the molecular landscape of osteoimmunological interactions that occur during aberrant osteochondral differentiation that could be useful for HO treatment.
2025-03-06 | GSE246445 | GEO
Project description:Heterotopic ossification (HO), usually following traumatic challenges, is initiated by the aberrant osteochondral differentiation of mesenchymal stem cell (MSC). However, the role of trauma-induced inflammatory exposure in MSC fate determination remains unclear. Here, we found that quiescent MSC transited into cycling MSC and later gave rise to chondrogenic (cMSC) and/or osteogenic (oMSC) commitment following either muscle or tendon injury via single-cell RNA sequencing and lineage tracing analysis. Further spatial transcriptome analysis revealed that cycling MSC, cMSC and oMSC resided in the inflammatory niche comprised of monocytes/macrophages, neutrophils, dendritic cells (DCs), NK cells, T and B lymphocytes. We uncovered the diversity of each type of immune cells during MSC development and demonstrated that macrophages, including M1 and M2 subtypes, dynamically promotes proliferation and osteochondral differentiation of MSCs. Additionally, neutrophils and NK cells are essential for cycling MSC transition from quiescent MSC. CD4+ and CD8+ T lymphocytes promotes chondrogenesis. CellchatDB analysis and regulon analysis identify several gene networks, which could be essential for aberrant MSC proliferation and osteochondral differentiation respectively. Collectively, our findings indicate that inflammation is necessary to regulate MSC fate and uncovered the molecular landscape of osteoimmunological interactions that occur during aberrant osteochondral differentiation that could be useful for HO treatment.
2025-03-06 | GSE246448 | GEO
Project description:scRNA and snATAC sequencing of cells harvested from the tendon injury site after a severe burn/tenotomy injury in Hoxa11 lineage traced mice allowed for differentation tracing of MSCs located in zeugopod after severe heterotopic ossification inducing injury. The use of immobilization also allowed us to determine the effects of limb immoblization on MSCs during aberrant wound healing.
2020-06-30 | GSE150995 | GEO
Project description:We have developed a protocol to generate hPSC-derived osteochondral fusions that mimick embryonic long bone diaphysis. hPSCs were first differentiated to chondroprogenitors and osteogenesis-committed early chondrocytes. Then they were centrifuged together to genrate a fusion construct. After cultured for 7 days in vitro, the fusion construct was transplanted under the kidney capsule of the NOD/SCID mice to generate a mature osteochondral fusion. The 4-week osteochondral fusion grafts contain full spectrum of cells during endochondral ossification, mimicking the in vivo growth plate tissues of early long bone diaphysis. To exam this tissue in single-cell level for comparison with the published datasets of the true human emrbyo, we conducted single-cell RNA sequencing on the 4-week osteochondral fusion grafts.
2025-02-21 | GSE275943 | GEO
Project description:Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR (db/db) and leptin (ob/ob) are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4, a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO cite, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Surprisingly, exogenous ANGPTL4 treatment not only promoted HO, but facilitated the transformation from white to brown adipose tissue in mice. These findings identify ANGPTL4 as a novel ligand for LepR to stimulate HO and regulate fat metabolism.
2024-07-03 | PXD043087 | Pride
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:Skeletal muscle atrophy is a consequence of many diseases, environmental insults, inactivity, age and injury. Atrophy is characterized by active degradation and removal of contractile proteins and a reduction in fiber size. Animal models have been extensively used to identify pathways leading to atrophic conditions. Here we have used genome-wide expression profiling analysis and quantitative PCR to identify the molecular changes that occur in two clinically relevant animal mouse models of muscle atrophy, hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7 and 14 days after insult. The total amount of muscle loss as measured by wet weight and muscle fiber size was equivalent between models, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tentomy resulted in the regulation of significantly more mRNA transcripts then casting. Analysis of the regulated genes and pathways suggest that the mechanism of atrophy is distinct between these models. The degradation following casting appears ubiquitin-proteasome-mediated while degradation following tenotomy appears lysosomal and matrix-metalloproteinase (MMP)-mediated. This data suggests that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat the atrophy seen under different conditions. Muscle atrophy was induced through two methods; unloading induced by tendon laceration (Tenotomy) and immobilization induced by hindlimb casting (Casting). For the tenotomy, eight week old male C57/B6 mice were anesthetized by ether inhalation and subsequent intramuscular injection of ketamine-xylazine (0.1 ml/g). The right Achilles tendon just proximal to the calcaneus was severed with a sterile scalpel. The mice were allowed to recover and move freely about their cage. An additional cohort of animals was sham operated (Sham) which involved isolation and manipulation of the Achilles tendon without laceration. For the casting, the right hindlimbs of eight week old male C57Bl/6 mice were immobilized through casting. After 2, 7 or 14 days, animals were sacrificed and the left and right gastrocnemius muscles were carefully removed, flash frozen in liquid nitrogen, and stored at -80°C for further processing. The left untreated legs served as controls. A group of naïve animals that received no treatment or manipulation was included as an additional control. Each group consisted of between 5 and 10 samples for a total of 111 individual samples.
2011-10-24 | E-GEOD-25908 | biostudies-arrayexpress
Project description:Background: Heterotopic ossification (HO), characterized by pathological bone formation in extra-skeletal tissues such as tendon, often results in debilitating tissue dysfunction. HO of tendons primarily arises from abnormal osteogenic differentiation of tendon stem cells following injury. Despite being a common clinical occurrence, the cellular and molecular mechanisms of tendon HO are poorly understood, and effective treatments remain elusive. Farnesol, a natural isoprenoid alcohol abundant in citrus fruits, lavender, and royal jelly, is known for its potent anti-inflammatory, antioxidant, and antitumor properties. However, its applications in tissue engineering are rarely explored, particularly in musculoskeletal repair. Here, we provide the first report on the therapeutic potential of Farnesol in attenuating tendon HO and elucidate the associated molecular mechanisms.Methods: This study evaluated the effects of Farnesol on osteogenic differentiation of tendon-derived stem cells using both in vitro and in vivo models. The molecular mechanisms underlying the therapeutic effects of Farnesol on tendon HO were revealed by RNA sequencing combined with network pharmacology analysis, identifying the GSTP1/MAPK axis as a potential target pathway. In vitro rescue experiments using a specific GSTP1 inhibitor were conducted to confirm whether Farnesol primarily exerted its therapeutic effects through GSTP1.Results: The results demonstrated significant effects of Farnesol on attenuating tendon HO both in vitro and in vivo. Combined analysis of transcriptomics and network pharmacology indicated that Farnesol functions by targeting the GSTP1/MAPK signaling axis. These findings were further validated by in vitro experiments using the GSTP1 inhibitor, which reversed the suppressive effects of Farnesol on osteogenesis.Conclusion: Farnesol inhibits the progression of post-traumatic tendon HO by targeting the GSTP1/MAPK pathway. These findings provide new insights into the potential of using Farnesol as a therapeutic agent for HO.
2026-01-31 | GSE317543 | GEO
Project description:The equine carpal osteochondral fragment model
| PRJEB53619 | ENA