Cross-talk between TGF-beta/SMAD and integrin signaling pathways in regulating hypertrophy of mesenchymal stem cell chondrogenesis under deferral dynamic compression

Zhang, Tianting; Wen, Feng; Wu, Yingnan; Goh, Graham S.; Ge, Zigang; Tan, Lay Poh; Hui, James; Yang, Zheng

doi:10.1016/j.biomaterials.2014.10.010

Cited by 107 publications

(84 citation statements)

References 59 publications

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“…TGF-β3 is an essential prochondrogenesis transcription factor. [40][41][42][43] Our study revealed that TGF-β3 was downregulated during osteogenesis and calcification of HAVICs. Smad3/RUNX2 and Wnt/β-cantenin are important pathways of osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 64%

Mir‐29b promotes human aortic valve interstitial cell calcification via inhibiting TGF‐β3 through activation of wnt3/β‐catenin/Smad3 signaling

Fang

Wang

Zheng³

et al. 2018

J of Cellular Biochemistry

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Herein, we hypothesized that pro‐osteogenic MicroRNAs (miRs) could play functional roles in the calcification of the aortic valve and aimed to explore the functional role of miR‐29b in the osteoblastic differentiation of human aortic valve interstitial cells (hAVICs) and the underlying molecular mechanism. Osteoblastic differentiation of hAVICs isolated from human calcific aortic valve leaflets obtained intraoperatively was induced with an osteogenic medium. Alizarin red S staining was used to evaluate calcium deposition. The protein levels of osteogenic markers and other proteins were evaluated using western blotting and/or immunofluorescence while qRT‐PCR was applied for miR and mRNA determination. Bioinformatics and luciferase reporter assay were used to identify the possible interaction between miR‐29b and TGF‐β3. Calcium deposition and the number of calcification nodules were pointedly and progressively increased in hAVICs during osteogenic differentiation. The levels of osteogenic and calcification markers were equally increased, thus confirming the mineralization of hAVICs. The expression of miR‐29b was significantly increased during osteoblastic differentiation. Furthermore, the osteoblastic differentiation of hAVICs was significantly inhibited by the miR‐29b inhibition. TGF‐β3 was markedly downregulated while Smad3, Runx2, wnt3, and β‐catenin were significantly upregulated during osteogenic induction at both the mRNA and protein levels. These effects were systematically induced by miR‐29b overexpression while the inhibition of miR‐29b showed the inverse trends. Moreover, TGF‐β3 was a direct target of miR‐29b. Inhibition of miR‐29b hinders valvular calcification through the upregulation of the TGF‐β3 via inhibition of wnt/β‐catenin and RUNX2/Smad3 signaling pathways.

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Section: Discussionmentioning

confidence: 64%

Mir‐29b promotes human aortic valve interstitial cell calcification via inhibiting TGF‐β3 through activation of wnt3/β‐catenin/Smad3 signaling

Fang

Wang

Zheng³

et al. 2018

J of Cellular Biochemistry

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“…The use of MSCs in cartilage tissue engineering can avoid some constraints of expanded mature chondrocytes, such as dedifferentiation and limited cell viability. Although great efforts have been made, the existing chondrogenic induction methods for MSCs are still quite inefficient (11). Worse still, endochondral ossification easily occurs in the formed cartilage tissues (9, 10).…”

Section: Discussionmentioning

confidence: 99%

Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating JNK and β‐catenin–related pathways

et al. 2019

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Cartilage engineering strategies using mesenchymal stem cells (MSCs) could provide preferable solutions to resolve long‐segment tracheal defects. However, the drawbacks of widely used chondrogenic protocols containing TGF‐β3, such as inefficiency and unstable cellular phenotype, are problematic. In our research, to optimize the chondrogenic differentiation of human umbilical cord MSCs (hUCMSCs), kartogenin (KGN) preconditioning was performed prior to TGF‐β3 induction. hUCMSCs were preconditioned with 1 µM of KGN for 3 d, sequentially pelleted, and incubated with TGF‐β3 for 28 d. Then, the expression of chondrogenesis‐ and ossification‐related genes was evaluated by immunohistochemistry and RT‐PCR. The underlying mechanism governing the beneficial effects of KGN preconditioning was explored by phosphorylated kinase screening and validated in vitro and in vivo using JNK inhibitor (SP600125) and β‐catenin activator (SKL2001). After KGN preconditioning, expression of fibroblast growth factor receptor 3, a marker of precartilaginous stem cells, was up‐regulated in hUCMSCs. Furthermore, the KGN‐preconditioned hUCMSCs efficiently differentiated into chondrocytes with elevated chondrogenic gene (SOX9, aggrecan, and collagen II) expression and reduced expression of ossifie genes (collagen X and MMP13) compared with hUCMSCs treated with TGF‐β3 only. Phosphokinase screening indicated that the beneficial effects of KGN preconditioning are directly related to an up‐regulation of JNK phosphorylation and a suppression of β‐catenin levels. Blocking and activating tests revealed that the prochondrogenic effects of KGN preconditioning was achieved mainly by activating the JNK/Runt‐related transcription factor (RUNX)1 pathway, and antiossific effects were imparted by suppressing the β‐catenin/RUNX2 pathway. Eventually, tracheal patches, based on KGN‐preconditioned hUCMSCs and TGF‐β3 encapsulated electrospun poly (l‐lactic acid‐co‐ε‐caprolactone)/collagen nanofilms, were successfully used for restoring tracheal defects in rabbit models. In summary, KGN preconditioning likely improves the chondrogenic differentiation of hUCMSCs by committing them to a precartilaginous stage with enhanced JNK phosphorylation and suppressed β‐catenin. This novel protocol consisting of KGN preconditioning and subsequent TGF‐β3 induction might be preferable for cartilage engineering strategies using MSCs.—Jing, H., Zhang, X., Gao, M., Luo, K., Fu, W., Yin, M., Wang, W., Zhu, Z., Zheng, J., He, X. Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating JNK and β‐catenin—related pathways. FASEB J. 33, 5641–5653 (2019). http://www.fasebj.org

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“…Smads have shown to function as regulators of chondrogenic differentiation of MSCs. Activation Smad 2 and 3 are dependent on the effect of TGF-β1 in the early stages of chondrogenesis (Zhang et al, 2015). Furumatsu et al demonstrated that Smad3 binds the transcription factor Sox9, thereby impairing chondrogenic differentiation (Furumatsu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Key transcription factors in the differentiation of mesenchymal stem cells

2016

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Mesenchymal stem cells (MSCs) are multipotent cells that represent a promising source for regenerative medicine. MSCs are capable of osteogenic, chondrogenic, adipogenic and myogenic differentiation. Efficacy of differentiated MSCs to regenerate cells in the injured tissues requires the ability to maintain the differentiation toward the desired cell fate. Since MSCs represent an attractive source for autologous transplantation, cellular and molecular signaling pathways and micro-environmental changes have been studied in order to understand the role of cytokines, chemokines, and transcription factors on the differentiation of MSCs. The differentiation of MSC into a mesenchymal lineage is genetically manipulated and promoted by specific transcription factors associated with a particular cell lineage. Recent studies have explored the integration of transcription factors, including Runx2, Sox9, PPARγ, MyoD, GATA4, and GATA6 in the differentiation of MSCs. Therefore, the overexpression of a single transcription factor in MSCs may promote trans-differentiation into specific cell lineage, which can be used for treatment of some diseases. In this review, we critically discussed and evaluated the role of transcription factors and related signaling pathways that affect the differentiation of MSCs toward adipocytes, chondrocytes, osteocytes, skeletal muscle cells, cardiomyocytes, and smooth muscle cells.

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Cross-talk between TGF-beta/SMAD and integrin signaling pathways in regulating hypertrophy of mesenchymal stem cell chondrogenesis under deferral dynamic compression

Cited by 107 publications

References 59 publications

Mir‐29b promotes human aortic valve interstitial cell calcification via inhibiting TGF‐β3 through activation of wnt3/β‐catenin/Smad3 signaling

Mir‐29b promotes human aortic valve interstitial cell calcification via inhibiting TGF‐β3 through activation of wnt3/β‐catenin/Smad3 signaling

Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating JNK and β‐catenin–related pathways

Key transcription factors in the differentiation of mesenchymal stem cells

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