NAP1L2 Drives Mesenchymal Stem Cell Senescence and Suppresses Osteogenic Differentiation [RNA-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166243 | GEO | 2021/02/06
REPOSITORIES: GEO
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Project description:Changes in these genes are probably a consequence of aging, and the real regulators governing BMSC senescence and osteogenesis are still unclear.In the current study, we report that nucleosome assembly-related protein NAP1L2 serves as an important regulator of both the senescence and osteogenic differentiation of BMSCs through inhibition of NF-κB signaling and recruitment of SIRT1 to deacetylate the H3K14ac level on promoters of osteogenic genes. Thus, targeting NAP1L2 using an aging antagonist such as NMN would benefit aging-related disease.
2021-02-06 | GSE166242 | GEO
Project description:Changes in these genes are probably a consequence of aging, and the real regulators governing BMSC senescence and osteogenesis are still unclear.In the current study, we report that nucleosome assembly-related protein NAP1L2 serves as an important regulator of both the senescence and osteogenic differentiation of BMSCs through inhibition of NF-κB signaling and recruitment of SIRT1 to deacetylate the H3K14ac level on promoters of osteogenic genes. Thus, targeting NAP1L2 using an aging antagonist such as NMN would benefit aging-related disease.
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Project description:Pathological processes like osteoporosis or steroid-induced osteonecrosis of the hip are accompanied by increased bone marrow adipogenesis. Such disorder of adipogenic/osteogenic differentiation, which affects also bone marrow derived mesenchymal stem cells (BMSCs) contributes to bone loss during aging. Therefore, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on osteogenic and adipogenic differentiation capacity of naïve hBMSCs.
2022-10-14 | PXD035845 | Pride
Project description:The treatment of bone defects caused by infection, trauma or neoplasms remains a clinical challenge. Autologous bone transplantation is limited by availability, donor site morbidity and surgical risk factors. This has given rise to stromal/stem-cell based therapy. Bone marrow derived stromal cells (BMSCs) have been studied to a large extent and show high regenerative potential but their use is limited by availability, donor site morbidity and the relatively low cell yield as they represent only <0.1% of cell harvested from bone marrow aspirate. At the same time, they are the closest mesenchymal stromal cells for bone tissue engineering given their tissue origin and, unlike other mesenchymal stromal cells, can support the formation of hematopoietic marrow. Adipose tissue derived stromal cells (ASCs) as part of the stromal vascular fraction of adipose tissue can as well undergo osteogenic differentiation but can be additionally isolated in a sufficient quantity from lipoaspirate after liposuction of abundant subcutaneous fat tissue. Here, it has been shown that there are no major differences in regard to proliferation or differentiation capacity of ASCs derived from subcutaneous fat of different anatomical regions. It has been shown that BMSCs are more prone to senescence during expansion and passage than ASCs and that ageing impacts proliferative capabilities of BMSCs more than that of ASCs while it has also been reported that osteogenic differentiation capacity is least impacted by age. Multiple studies have compared the characteristics of these two mesenchymal stromal cells in regard to bone tissue engineering in vitro. Most studies point to inferior extracellular matrix mineralization and lower expression of key osteogenic transcription markers like Runx2 in osteogenic differentiated ASCs compared to BMSCs. On the other hand, a study by Rath et al. found contrary results using particular culturing conditions like 3D bioglass scaffolds. An intraindividual comparison of human MSCs of three donors cultured on decellularized porcine bone confirmed superior osteogenic capacity of BMSCs compared to ASCs. In contrast to BMSCs, ASCs were not able to induce heterogenic ossification in a mouse model. In a sheep tibia defect model application of BMSCs resulted in a significantly higher amount of newly formed bone tissue. Importantly, Osteogenic differentiated ASCs do not support the formation of a hematopoietic marrow. Proteomics enables large-scale analysis of proteins present in a cell type and can be used to identify differentially regulated key proteins in a comparative approach. A comparative proteomic analysis of BMSCs and ASCs by Roche et al. in 2009 identified 556 proteins with 78% of these not being differentially regulated between these two cell populations, regarded as high similarity. Another comparative proteomic study of 2016 by Jeon et al. found 90 differentially regulated proteins out of 3000 total identified proteins. Both studies do not specify a number of different tissue donors and in part using cell lines. Looking for differences upon osteogenic differentiation, transcriptomic comparison of osteogenic differentiated porcine ASCs and BMSCs has been performed, resulting in 21 differentially expressed genes after 21 days of osteogenic culture conditions. Still, it remains unanswered, which are the key distinctive features of osteogenic differentiated ASCs and BMSCs at protein level that might help address the abovementioned weaknesses of ASCs in bone tissue engineering/regeneration for translational research. To overcome this need, an intraindividual comparative DIA based proteomic analysis of osteogenic differentiated human BMSC and ASCs was performed in this study.
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Project description:Bone marrow stromal cells (BMSCs) can be expanded by serial passage, but expansion is limited by cell senescence. The nature of changes associated with BMSC serial passages was assessed. Transcriptome analysis of 10 early and 15 late passage samples from 5 subjects revealed 2193 differentially expressed genes; those highly expressed in early passage cells were overrepresented in skeletal system development, embryonic morphogenesis, tube morphogenesis, etc, while those highly expressed in the late passage BMSCs were overrepresented in nucleosome assembly; chromatin assembly, DNA packaging, etc. 57 BMSC samples from 7 donors were further analyzed for the transition from an early to late passage; 155 genes were highly correlated with BMSC senescence and a set of 24 genes was predictive of BMSCs lifespan. The change from an early to a late passage molecular signature occurred between passage 3 and 5. In contrast, senescence associated beta-galactosidase staining began to increase after passage 6 or 7 and colony formation efficiency began to fall after passage 7. These data indicated that the onset of molecular changes associated with BMSC passage varied among individuals and preceded changes in commonly used indicators of BMSC senescence. The set of 24 BMSC lifespan predictive genes will be useful in assessing the quality of clinical BMSC products.
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2024-06-01 | GSE234060 | GEO
Project description:Background: Dicalcium cilicate (C2S) is a potent biomaterial for bone regeneration application. Circular RNA (circRNAs) plays crucial role in osteogenic differentiation of mesenchymal stem cells (MSCs) and bone defect healing. In this study, we aim to elucidate the differential expression of circ_RNAs and mRNAs in C2S-treated MSCs, the role of circ_1983 in C2S-mediated bone regeneration, and its mechanism. Methods: The effect of C2S on osteogenic differentiation of mice bone marrow-derived MSCs (BMSCs) and rat cranial bone defect healing were analyzed. Differential expression of circ-RNAs and mRNAs in C2S-treated BMSCs were profiled by RNA-sequencing. The interaction between circ_1983 and miR-6931 was confirmed by pull-down and dual luciferase reporter assays. ceRNA function of circ_1983 via sponging miR-6931 and targeting Gas7 mRNA expression in BMSCs was analyzed by miRanda (http://www.microrna.org/microrna/). Role of circ_1983 in C2S-induced osteogenic differentiation of BMSCs was analyzed by shRNA-mediated knockdown of circ_1983. Results: C2S enhanced osteogenic differentiation of BMSCs and bone defect healing. CircRNAs (total 1384) and mRNAs (total 1725) were differentially upregulated in C2S-treated BMSCs. Upregulated circRNAs and ceRNA-interaction networks were associated with osteogenesis-related signaling pathways, i.e. MAPK, PI3K-Akt. RNA-sequencing and qRT-PCR results confirmed upregulation of circ_1983 in C2S-tretaed BMSCs. Circ_1983 showed ceRNA effect by sponging miR-6931 and overexpressing Gas mRNA that enhanced Runx2 expression and promoted osteogenic differentiation of BMSCs. Knockdown of circ_1983 inhibited the C2S-induced osteogenic differentiation of BMSCs. Interpretation: C2S-induced circ_1983 upregulation in BMSCs sponges miR-6931 and targets Gas7 gene to enhance Runx2 expression thereby promotes osteogenic differentiation and bone regeneration.
2021-04-12 | GSE140273 | GEO
Project description:Age-induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases risk for bone fractures. Despite epidemiology studies reporting concurrent development of vascular- and bone diseases in the elderly, the underlying mechanisms for the vascular-bone cross-talk in aging are largely unknown. In this study, we show that accelerated endothelial aging deteriorates bone tissue through paracrine repression of Wnt-driven-axis in BMSCs. Here, we utilize physiologically aged mice in conjunction with our transgenic endothelial progeria mouse model (Hutchinson-Gilford progeria syndrome; HGPS) that displays hallmarks of an aged bone marrow vascular niche. We find bone defects associated with diminished BMSC osteogenic differentiation that implicate the existence of angiocrine factors with long-term inhibitory effects. microRNA-transcriptomics of HGPS-patient plasma combined with aged-vascular niche analyses in progeria mice reveal abundant secretion of Wnt-repressive microRNA-31-5p. Moreover, we show that inhibition of microRNA-31-5p as well as selective Wnt-activator CHIR99021 boost the osteogenic potential of BMSCs through de-repression and activation of the Wnt-signalling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave ground for microRNA-based therapies of bone loss in elderly.
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