TGF-Beta Induced Key Genes of Osteogenic and Adipogenic Differentiation in Human Mesenchymal Stem Cells and MiRNA–mRNA Regulatory Networks

Du, Genfa; Cheng, Xinyuan; Zhang, Zhen; Han, Linjing; Wu, Keliang; Li, Yongjun; Lin, Xiaotong

doi:10.3389/fgene.2021.759596

Cited by 18 publications

(12 citation statements)

References 49 publications

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“…Both BMP-2 and TGF-β have also been identified in human mesenchymal stem cells. (45) The reduction in bone mass due to osteoclastic activity, found in the present study, is consistent with results of a recent communication examining the role of menin in bone by disrupting the MEN1 gene at different stages of the osteoblast lineage. (18) However, in that study, the mutant Men1 created after Cremediated recombination in all mouse strains only lacked exon 3 in contrast to our model, which is deficient for exons 3-8.…”

Section: Discussionsupporting

confidence: 93%

Genetic Deletion of Menin in Mouse Mesenchymal Stem Cells: An Experimental and Computational Analysis

et al. 2022

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Loss-of-function mutations in the MEN1 tumor-suppressor gene cause the multiple endocrine neoplasia type 1 syndrome. Menin, the MEN1 gene product, is expressed in many tissues, including bone, where its function remains elusive. We conditionally inactivated menin in mesenchymal stem cells (MSCs) using paired-related homeobox 1 (Prx1)-Cre and compared resultant skeletal phenotypes of Prx1-Cre;Men1 f/f menin-knockout mice (KO) and wild-type controls using in vivo and in vitro experimental approaches and mechanics simulation. Dual-energy X-ray absorptiometry demonstrated significantly reduced bone mineral density, and 3-dimensional micro-CT imaging revealed a decrease in trabecular bone volume, altered trabecular structure, and an increase in trabecular separation in KO mice at 6 and 9 months of age. Numbers of osteoblasts were unaltered, and dynamic histomorphometry demonstrated unaltered bone formation; however, osteoclast number and activity and receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) mRNA profiles were increased, supporting increased osteoclastogenesis and bone resorption. In vitro, proliferative capabilities of bone marrow stem cells and differentiation of osteoblasts and mineralization were unaltered; however, osteoclast generation was increased. Gross femur geometrical alterations observed included significant reductions in length and in mid-metaphyseal cross-sectional area. Atomic force microscopy demonstrated significant decreases in elasticity of both cortical and trabecular bone at the nanoscale, whereas three-point bending tests demonstrated a 30% reduction in bone stiffness; finite element analysis showed morphological changes of the femur microgeometry and a significantly diminished femur flexural rigidity. The biomechanical results demonstrated the detrimental outcome of the accelerated osteoclastic bone resorption. Our studies have a twofold implication; first, MEN1 deletion from MSCs can negatively regulate bone mass and bone biomechanics, and second, the experimental and computational biomechanical analyses employed in the present study should be applicable for improved phenotypic characterization of murine bone. Furthermore, our findings of critical menin function in bone may underpin the more severe skeletal phenotype found in hyperparathyroidism associated with loss-of-function of the MEN1 gene.

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Section: Discussionsupporting

confidence: 93%

Genetic Deletion of Menin in Mouse Mesenchymal Stem Cells: An Experimental and Computational Analysis

et al. 2022

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“…The improved expression of TGFβ1 at the early stage of cell growth (D1) and the reduction at D7 is coherent with previous reports, suggesting that this gene is important during the early differentiation of osteoblasts, but it inhibits their late differentiation into osteocytes [ 42 , 43 ]. TGFβ1 plays an important role in the proliferation and early differentiation of osteoblasts improving intracellular Ca +2 transport.…”

Section: Resultssupporting

confidence: 91%

Physiologic Response Evaluation of Human Foetal Osteoblast Cells within Engineered 3D-Printed Polylactic Acid Scaffolds

Rizzo

Palermo

Alibrandi

et al. 2023

Biology

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Large bone defect treatments have always been one of the important challenges in clinical practice and created a huge demand for more efficacious regenerative approaches. The bone tissue engineering (BTE) approach offered a new alternative to conventional bone grafts, addressing all clinical needs. Over the past years, BTE research is focused on the study and realisation of new biomaterials, including 3D-printed supports to improve mechanical, structural and biological properties. Among these, polylactic acid (PLA) scaffolds have been considered the most promising biomaterials due to their good biocompatibility, non-toxic biodegradability and bioresorbability. In this work, we evaluated the physiological response of human foetal osteoblast cells (hFOB), in terms of cell proliferation and osteogenic differentiation, within oxygen plasma treated 3D-printed PLA scaffolds, obtained by fused deposition modelling (FDM). A mechanical simulation to predict their behaviour to traction, flexural or torque solicitations was performed. We found that: 1. hFOB cells adhere and grow on scaffold surfaces; 2. hFOB grown on oxygen plasma treated PLA scaffolds (PLA_PT) show an improvement of cell adhesion and proliferation, compared to not-plasma treated scaffolds (PLA_NT); 3. Over time, hFOB penetrate along strands, differentiate, and form a fibrous matrix, tissue-like; 4. 3D-printed PLA scaffolds have good mechanical behaviour in each analysed configuration. These findings suggest that 3D-printed PLA scaffolds could represent promising biomaterials for medical implantable devices in the orthopaedic field.

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“…Expression of TGF-β by ESCC CAFs, furthermore, confers resistance to multiple chemotherapeutics (cisplatin, carboplatin, docetaxel) [ 129 ]. While the various functions of TGF-β in the TME were discussed previously (e.g., [ 20 , 130 ]), analysis of the Protein–Protein Interaction (PPI) network implicated CTGF (CNN2), IGF-1, BMP2, MMP13, TGF-β3, MMP3 and SERPINE1 (PAI-1) as major hub genes in the TGF-β-induced differentiation of human mesenchymal stem cells [ 131 ]. The protumorigenic actions of TGF-β likely involve the coordination of multiple signaling pathways in both CAF and non-CAF target cells within the TME.…”

Section: Cafs Confer Resistance To Chemotherapymentioning

confidence: 99%

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

Czekay

Cheon

Samarakoon

et al. 2022

Cancers

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Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.

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TGF-Beta Induced Key Genes of Osteogenic and Adipogenic Differentiation in Human Mesenchymal Stem Cells and MiRNA–mRNA Regulatory Networks

Cited by 18 publications

References 49 publications

Genetic Deletion of Menin in Mouse Mesenchymal Stem Cells: An Experimental and Computational Analysis

Genetic Deletion of Menin in Mouse Mesenchymal Stem Cells: An Experimental and Computational Analysis

Physiologic Response Evaluation of Human Foetal Osteoblast Cells within Engineered 3D-Printed Polylactic Acid Scaffolds

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

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