Gastrointestinal stromal tumors (GISTs) are the main stromal tumors of the digestive tract. Extragastrointestinal stromal tumors (EGISTs) typically originate outside the gastrointestinal tract; are ...not associated with the stomach or intestinal walls; and are mainly derived from the mesentery, peritoneum, posterior peritoneum, bladder, and scrotum. However, EGISTs from the prostate are rare. Here, we present a case of EGIST that passed off in the prostate of a 62-year-old man. The patient undergoes transrectal guided trans-perineal prostate puncture, and pathological reports suggest a GIST. Tumor cells are spindle-shaped, and no obvious neoplastic necrosis is seen in the sections. Immunohistochemical results are robustly positive for CD117, DOG-1, and CD34 expression. The patient had a good prognosis after treatment with imatinib, no recurrence and no metastases after six months of follow-up, and the prognosis was good. This article also provides a literature review and discussion of the treatment of EGISTs.
To study whether TGF-β1/IL-11/MEK/ERK (TIME) signaling mediates senescence-associated pulmonary fibrosis (SAPF) in Bmi-1-deficient (Bmi-1
) mice and determines the major downstream mediator of Bmi-1 ...and crosstalk between p16
and reactive oxygen species that regulates SAPF, phenotypes were compared among 7-week-old p16
and Bmi-1 double-knockout, N-acetylcysteine (NAC)-treated Bmi-1
, Bmi-1
, and wild-type mice. Pulmonary fibroblasts and alveolar type II epithelial (AT2) cells were used for experiments. Human pulmonary tissues were tested for type Ι collagen, α-smooth muscle actin (α-SMA), p16
, p53, p21, and TIME signaling by using enzyme-linked immunosorbent assay (ELISA). Our results demonstrated that Bmi-1 deficiency resulted in a shortened lifespan, ventilatory resistance, poor ventilatory compliance, and SAPF, including cell senescence, DNA damage, a senescence-associated secretory phenotype and collagen overdeposition that was mediated by the upregulation of TIME signaling. The signaling stimulated cell senescence, senescence-related secretion of TGF-β1 and IL-11 and production of collagen 1 by pulmonary fibroblasts and the epithelial-to-mesenchymal transition of AT2 cells. These processes were inhibited by anti-IL-11 or the MEK inhibitor PD98059. NAC treatment prolonged the lifespan and ameliorated pulmonary dysfunction and SAPF by downregulating TIME signaling more than p16
deletion by inhibiting oxidative stress and DNA damage and promoting ubiquitin-proteasome degradation of p16
and p53. Cytoplasmic p16
accumulation upregulated MEK/ERK signaling by inhibiting the translocation of pERK1/2 (Thr202/Tyr204) from the cytoplasm to the nucleus in senescent fibroblasts. The accumulation of collagen 1 and α-SMA in human lungs accompanied by cell senescence may be mediated by TIME signaling. Thus, this signaling in aging fibroblasts or AT2 cells could be a therapeutic target for preventing SAPF.
We previously demonstrated that Bmi1 deficiency leads to osteoporosis phenotype by inhibiting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs), but it is ...unclear whether overexpression of Bmi1 in MSCs stimulates skeletal development and rescues Bmi1 deficiency‐induced osteoporosis. To answer this question, we constructed transgenic mice (Bmi1Tg) that overexpressed Bmi1 driven by the Prx1 gene and analyzed their skeletal phenotype differences with that of wild‐type littermates. We then hybridized Bmi1Tg to Bmi1−/− mice to generate Bmi1−/− mice overexpressing Bmi1 in MSCs and compared their skeletal phenotypes with those of Bmi1−/− and wild‐type mice using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods. Bmi1Tg mice exhibited enhanced bone growth and osteoblast formation, including the augmentation of bone size, cortical and trabecular volume, number of osteoblasts, alkaline phosphatase (ALP)‐positive and type I collagen‐positive areas, number of total colony forming unit fibroblasts (CFU‐f) and ALP+ CFU‐f, and osteogenic gene expression levels. Consistently, MSC overexpressing Bmi1 in the Bmi1−/− background not only largely reversed Bmi1 systemic deficiency‐induced skeletal growth retardation and osteoporosis, but also partially reversed Bmi1 deficiency‐induced systemic growth retardation and premature aging. To further explore the mechanism of action of MSCs overexpressing Bmi1 in antiosteoporosis and antiaging, we examined changes in oxidative stress and expression levels of p16 and p19. Our results showed that overexpression of Bmi1 in MSCs inhibited oxidative stress and downregulated p16 and p19. Taken together, the results of this study indicate that overexpression of Bmi1 in MSCs exerts antiaging and antiosteoporosis effects by inactivating p16/p19 signaling and inhibiting oxidative stress. Stem Cells 2019;37:1200–1211
Bmi1 overexpression in mesenchymal stem cells can inactivate p16/p19 signaling and inhibit oxidative stress, stimulate mesenchymal stem cell proliferation and differentiation into osteoblasts, subsequently enhancing osteoblastic bone formation to exert an antiosteoporosis effect.
Single-cell RNA sequencing (scRNA-seq) enables specific profiling of cell populations at single-cell resolution. The osteoimmunology microenvironment in the occurrence and development of ...periodontitis remains poorly understood at the single-cell level. In this study, we used single-cell transcriptomics to comprehensively reveal the complexities of the molecular components and differences with counterparts residing in periodontal tissues.
We performed scRNA-seq to identify 51248 single cells from healthy controls (n=4), patients with severe chronic periodontitis (n=5), and patients with severe chronic periodontitis after initial periodontal therapy within 1 month (n=3). Uniform manifold approximation and projection (UMAP) were further conducted to explore the cellular composition of periodontal tissues. Pseudotime cell trajectory and RNA velocity analysis, combined with gene enrichment analysis were used to reveal the molecular pathways underlying cell fate decisions. CellPhoneDB were performed to identify ligand-receptor pairs among the major cell types in the osteoimmunology microenvironment of periodontal tissues.
A cell atlas of the osteoimmunology microenvironment in periodontal tissues was characterized and included ten major cell types, such as fibroblasts, monocytic cells, endothelial cells, and T and B cells. The enrichment of
fibroblasts with high expression of
, and
was detected in patients with periodontitis compared to healthy individuals. The fractions of
mesenchymal stem cells (MSCs),
pre-osteoblasts (pre-OBs), and
osteoblasts decreased significantly in response to initial periodontal therapy. In addition,
MSC-like pericytes could convert their identity into a pre-OB state during inflammatory responses even after initial periodontal therapy confirmed by single-cell trajectory. Moreover, we portrayed the distinct subtypes of monocytic cells and abundant endothelial cells significantly involved in the immune response. The heterogeneity of T and B cells in periodontal tissues was characterized. Finally, we mapped osteoblast/osteoclast differentiation mediators to their source cell populations by identifying ligand-receptor pairs and highlighted the effects of Ephrin-Eph signaling on bone regeneration after initial periodontal therapy.
Our analyses uncovered striking spatiotemporal dynamics in gene expression, population composition, and cell-cell interactions during periodontitis progression. These findings provide insights into the cellular and molecular underpinning of periodontal bone regeneration.
Recent studies have demonstrated that several long non-coding RNAs (lncRNAs) play an important role in the occurrence and development of osteosarcoma (OS). However, more lncRNAs and their mechanisms ...in regulating growth and migration of OS cells remain to be investigated. In this study, we identified an lncRNA called DUXAP10 by analysis of GEO data, which was significantly up-regulated in OS tissues and cell lines. Experiments in vitro revealed that lncRNA DUXAP10 promoted proliferation, migration, and invasion of OS cells and inhibited their apoptosis. We also demonstrated that DUXAP10 promoted the formation and growth of OS by tumor formation assay. Furthermore, SOX18 was identified as a critical downstream target of DUXAP10 by transcriptome RNA-seq. Mechanistically, DUXAP10 mainly localized in cytoplasm and could specifically bind to HuR to increase the stability of SOX18 mRNA. Meanwhile, SOX18 knockdown largely reversed increased proliferation of OS cells induced by DUXAP10 overexpression. Findings from this study indicate that lncRNA DUXAP10 can act as an oncogene in osteosarcoma by binding HuR to up-regulate the expression of SOX18 at a post-transcriptional level, which may provide a new target for OS clinical diagnosis and treatment.
We used mice with targeted deletion of 25-hydroxyvitamin D-1 α-hydroxylase 1α(OH)ase(-/-) to investigate whether 1,25(OH)2D3 deficiency results in male infertility mediated by 1,25(OH)2D3 or ...extracellular calcium and phosphorus. Male 1α(OH)ase(-/-) and their wild-type littermates fed either a normal diet or a rescue diet from weaning were mated at 6-14 wk of age with female wild-type mice on the same diet. The fertility efficiency of females was analyzed, and the reproductive phenotypes of males were evaluated by histopathological and molecular techniques. Hypocalcemic and hypophosphatemic male 1α(OH)ase(-/-) mice on a normal diet developed infertility characterized by hypergonadotropic hypogonadism, with downregulation of testicular calcium channels, lower intracellular calcium levels, decreased sperm count and motility, and histological abnormalities of the testes. The proliferation of spermatogenic cells was decreased with downregulation of cyclin E and CDK2 and upregulation of p53 and p21 expression, whereas apoptosis of spermatogenic cells was increased with upregulation of Bax and p-caspase 3 expression and downregulation of Bcl-xl expression. When serum calcium and phosphorus were normalized by the rescue diet, the defective reproductive phenotype in the male 1α(OH)ase(-/-) mice, including the hypergonadotropic hypogonadism, decreased sperm count and motility, histological abnormalities of testis, and defective spermatogenesis, was reversed. These results indicate that the infertility seen in male 1,25(OH)2D3-deficient mice is not a direct effect of active vitamin D deficiency on the reproductive system but is an indirect effect mediated by extracellular calcium and phosphorus.
B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) deficiency (Bmi-1−/−) leads to an osteoporotic phenotype with a significant downregulation of Sirt1 protein expression. ...Sirtuin 1 (Sirt1) haploinsufficiency results in a bone loss by decreased bone formation; however, it is unclear whether Sirt1 overexpression in mesenchymal stem cells (MSCs) plays an anti-osteoporotic role. The aim of the study is to identify whether the overexpression of Sirt1 in MSCs could restore skeletal growth retardation and osteoporosis in Bmi-1 deficient mice.
We used our new generated transgenic mouse model that overexpresses Sirt1 in its MSCs (Sirt1TG) to cross with Bmi-1−/− mice to generate Bmi-1−/− mice with Sirt1 overexpression in MSCs, and compared their skeletal metabolism with those of their Bmi-1−/− and wild-type (WT) littermates (6 mice for each genotype) at 4 weeks of age using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods.
The levels of expression for Sirt1 were noticeably higher in the skeletal tissue of Sirt1TG mice than in those of WT mice. In Comparison to WT mice, the body weight and size, skeletal size, bone volume, osteoblast number, alkaline phosphatase and type I collagen positive areas, osteogenic related gene expression levels were all significantly increased in the Sirt1TG mice. Overexpression of Sirt1 in Bmi-1−/− mouse MSCs resulted in a longer lifespan, improved skeletal growth and significantly increased bone mass by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption in the Bmi-1−/− mice, although the defects were not completely restored. Furthermore, Sirt1 overexpression in MSCs reduced the acetylation level of FOXO3a (Forkhead box O3a), increasing levels of expression for FOXO3a and SOD2 (Superoxide dismutase 2) in bony tissue, enhanced osteogenesis and reduced osteogenic cell senescence. We also demonstrated that nicotinamide, a Sirt1 inhibitor, blocks the effect of overexpression of Sirt1 in MSCs on osteogenesis and osteogenic cell senescence.
Taken together, these results demonstrate that Sirt1 overexpression in MSCs increased the osteoblastic bone formation and partially restores the defects in skeletal growth and osteogenesis in Bmi-1−/− mice by FOXO3a deacetylation and oxidative stress inhibition. Our data support the proposal that Sirt1 is a target for promoting bone formation as an anabolic approach for the treatment of osteoporosis.
•Sirt1 overexpression in MSCs promotes osteoblastic bone formation.•Sirt1 overexpression in MSCs reduces the acetylation level of FOXO3a.•Sirt1 overexpression in MSCs prevents bone loss in Bmi-1 deficient mice.•Sirt1 overexpression in MSCs restores the redox balance in Bmi-1 deficient mice.•NAM blocks the effect of overexpression of Sirt1 on osteogenesis and cell senescence.
Abstract
Bone marrow mesenchymal stem cells (BMSCs) are indispensable cells constituting the bone marrow microenvironment that are generally recognized as being involved in the development and ...progression of osteosarcoma (OS). To explore whether mTORC2 signaling inhibition in BMSCs suppressed OS growth and tumor-caused bone destruction, 3-month-old littermates genotyped Rictorflox/flox or Prx1-cre; Rictorflox/flox (with same gender) were injected with K7M2 cells in the proximal tibia. After 40 days, bone destruction was alleviated in Prx1-cre; Rictorflox/flox mice, as observed on X-ray and micro-CT. This was accompanied by decreased serum N-terminal propeptide of procollagen type I (PINP) levels and reduced tumor bone formation in vivo. Interactions between K7M2 and BMSCs were studied in vitro. Rictor-deficient BMSCs, which were cultured in tumor-conditioned medium (TCM), caused reduced bone proliferation and suppressed osteogenic differentiation. Moreover, compared with the control group, K7M2 cells cultured in BCM (culture medium extracted from Rictor-deficient BMSCs) displayed less proliferation, migration, and invasion, and attenuated osteogenic activity. Forty types of cytokines were then analyzed by mouse cytokine array and decreased levels CCL2/3/5 and interleukin-16 were detected in Rictor-deficient BMSCs. These results suggested that inhibition of mTORC2 (Rictor) signaling pathway in BMSCs exerted anti-OS effects through 2 mechanisms: (1) by suppressing the proliferation and osteogenic differentiation of BMSCs induced by OS to alleviate bone destruction; (2) by reducing the secretion of cytokines by BMSCs, which are closely related to OS cell growth, migration, invasion, and tumorigenic osteogenesis.
Graphical abstract
Graphical Abstract
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