TGF-β1, GDF-5, and BMP-2 Stimulation Induces Chondrogenesis in Expanded Human Articular Chondrocytes and Marrow-Derived Stromal Cells

Murphy, Meghan K.; Huey, Daniel J.; Hu, Jerry C.; Athanasiou, Kyriacos A.

doi:10.1002/stem.1890

Cited by 138 publications

(142 citation statements)

References 62 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…Mesenchymal condensation has been adapted into selfassembly methods to enhance cartilage formation in vitro (10,11). TGF-β and thyroxine, potent effectors of cartilage maintenance and chondrocyte terminal differentiation, have been used in chondrogenic and hypertrophic induction regimens to guide MSC differentiation (4,14,(17)(18)(19)(20)(21)(22). Thus, we chose these two factors as culture supplements.…”

Section: Discussionmentioning

confidence: 99%

“…Our group and others have shown that self-assembly methods recapitulated mesenchymal condensation and enhanced chondrogenesis of MSCs in vitro (10)(11)(12). Still, standard isotropic culture fails to recapitulate the spatiotemporal gradients present during native development (3,9,13,14). Cartilage formed by MSCs is poorly organized and prone to endochondral ossification in vivo (4,15).…”

mentioning

confidence: 98%

See 1 more Smart Citation

Recapitulation of physiological spatiotemporal signals promotes in vitro formation of phenotypically stable human articular cartilage

Wei

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Standard isotropic culture fails to recapitulate the spatiotemporal gradients present during native development. Cartilage grown from human mesenchymal stem cells (hMSCs) is poorly organized and unstable in vivo. We report that human cartilage with physiologic organization and in vivo stability can be grown in vitro from self-assembling hMSCs by implementing spatiotemporal regulation during induction. Self-assembling hMSCs formed cartilage discs in Transwell inserts following isotropic chondrogenic induction with transforming growth factor β to set up a dual-compartment culture. Following a switch in the basal compartment to a hypertrophic regimen with thyroxine, the cartilage discs underwent progressive deep-zone hypertrophy and mineralization. Concurrent chondrogenic induction in the apical compartment enabled the maintenance of functional and hyaline cartilage. Cartilage homeostasis, chondrocyte maturation, and terminal differentiation markers were all up-regulated versus isotropic control groups. We assessed the in vivo stability of the cartilage formed under different induction regimens. Cartilage formed under spatiotemporal regulation in vitro resisted endochondral ossification, retained the expression of cartilage markers, and remained organized following s.c. implantation in immunocompromised mice. In contrast, the isotropic control groups underwent endochondral ossification. Cartilage formed from hMSCs remained stable and organized in vivo. Spatiotemporal regulation during induction in vitro recapitulated some aspects of native cartilage development, and potentiated the maturation of self-assembling hMSCs into stable and organized cartilage resembling the native articular cartilage.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Recapitulation of physiological spatiotemporal signals promotes in vitro formation of phenotypically stable human articular cartilage

Wei

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Aggrecan and COL2A1 are proliferative chondrocyte makers that essential to normal cartilage function. TGF-β1 promotes osteogenesis and chondrogenesis, and enhances the synthesis of extracellular matrix protein, including aggrecan, type II collagen, and cartilage oligomeric matrix protein (Hiraki et al 1988;Morales and Roberts 1988;Redini et al 1988;Galera et al 1992;Recklies et al 1998;Wang et al 2014;Murphy et al 2015;Yoon et al 2015). Overexpression of TGF-β1 improved chondrocytes phenotype, function, and proliferation, even after several generations (Tang et al 2017).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-483-5p Modulates the Expression of Cartilage-Related Genes in Human Chondrocytes through Down-Regulating TGF-<i>β</i>1 Expression

Wei

et al. 2017

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Transforming growth factor-β1 (TGF-β1) has been reported to improve chondrocytes phenotype and function. The expression levels of microRNA-483-5p (miR-483-5p), a potential regulator of TGF-β signaling pathway, were elevated in chondrocytes of patients with osteoarthritis. In this study, we aimed to explore the role of miR-483-5p for the expression of cartilage-related genes in chondrocytes. Human chondrocytes were harvested from femoral condyle and tibial plateau of different donors (n = 10) following amputation due to sarcomas not involving the joint space. The expression levels of miR-483-5p and TGF-β1 mRNA were measured by qRT-PCR. Runt-related transcription factor 2 (RUNX2) is a transcription factor involved in chondrocyte differentiation, and type II collagen-degrading matrix metalloproteinase13 (MMP13) contributes to cartilage degradation. qRT-PCR was also used to measure the levels of RUNX2 and MMP-13 mRNAs, as well as type II collagen alpha 1 (COL2A1) and aggrecan mRNAs. COL2A1 and aggrecan are major cartilage extracellular matrix proteins that are essential for normal cartilage function. The expression levels of miR-483-5p were significantly increased in chondrocytes from Passage 0 to 2, whereas the expression levels of TGF-β1 mRNA were marginally decreased. Passage 1 chondrocytes were employed for following experiments. MiR-483-5p overexpression reduced TGF-β1 expression, while miR-483-5p knockdown dramatically elevated TGF-β 1 expression both at mRNA and protein levels. Further, miR-483-5p overexpression significantly decreased the levels of COL2A1 and aggrecan mRNAs, and increased those of RUNX2 and MMP13 mRNAs, by down-regulating TGF-β1 expression. These findings suggest that modulating miR-483-5p expression may contribute to maintaining the cartilage tissues.

show abstract

“…These are members of the transforming growth factor-β (TGF-β) superfamily (including Bone Morphogenetic Proteins-BMPs, Growth and Differentiation Factors-GDFs [101]), fibroblast growth factor (FGF) family, insulin-like growth factor-1 (IGF-1), and plateletderived growth factor (PDGF) [8]. Growth factors act through modulation of the local microenvironment (making it chondroinducive or osteoinducive), anabolic cellular effects, and increased matrix production.…”

Section: Growth Factorsmentioning

confidence: 99%

Mimetic Hierarchical Approaches for Osteochondral Tissue Engineering

Gadjanski

2018

Osteochondral Tissue Engineering

View full text Add to dashboard Cite

In order to engineer biomimetic osteochondral (OC) construct, it is necessary to address both the cartilage and bone phase of the construct, as well as the interface between them, in effect mimicking the developmental processes when generating hierarchical scaffolds that show gradual changes of physical and mechanical properties, ideally complemented with the biochemical gradients. There are several components whose characteristics need to be taken into account in such biomimetic approach, including cells, scaffolds, bioreactors as well as various developmental processes such as mesenchymal condensation and vascularization, that need to be stimulated through the use of growth factors, mechanical stimulation, purinergic signaling, low oxygen conditioning, and immunomodulation. This chapter gives overview of these biomimetic OC system components, including the OC interface, as well as various methods of fabrication utilized in OC biomimetic tissue engineering (TE) of gradient scaffolds. Special attention is given to addressing the issue of achieving clinical size, anatomically shaped constructs. Besides such neotissue engineering for potential clinical use, other applications of biomimetic OC TE including formation of the OC tissues to be used as high-fidelity disease/ healing models and as in vitro models for drug toxicity/efficacy evaluation are covered. Highlights Biomimetic OC TE uses "smart" scaffolds able to locally regulate cell phenotypes and dual-flow bioreactors for two sets of conditions for cartilage/ bone Protocols for hierarchical OC grafts engineering should entail mesenchymal condensation for cartilage and vascular component for bone Immunomodulation, low oxygen tension, purinergic signaling, time dependence of stimuli application are important aspects to consider in biomimetic OC TE Mimetic Hierarchical Approaches for Osteochondral Tissue Engineering Ivana GadjanskiAbstract In order to engineer biomimetic osteochondral (OC) construct, it is necessary to address both the cartilage and bone phase of the construct, as well as the interface between them, in effect mimicking the developmental processes when generating hierarchical scaffolds that show gradual changes of physical and mechanical properties, ideally complemented with the biochemical gradients. There are several components whose characteristics need to be taken into account in such biomimetic approach, including cells, scaffolds, bioreactors as well as various developmental processes such as mesenchymal condensation and vascularization, that need to be stimulated through the use of growth factors, mechanical stimulation, purinergic signaling, low oxygen conditioning, and immunomodulation. This chapter gives overview of these biomimetic OC system components, including the OC interface, as well as various methods of fabrication utilized in OC biomimetic tissue engineering (TE) of gradient scaffolds. Special attention is given to addressing the issue of achieving clinical size, anatomically shaped constructs. Besides such neotissue en...

show abstract

TGF-β1, GDF-5, and BMP-2 Stimulation Induces Chondrogenesis in Expanded Human Articular Chondrocytes and Marrow-Derived Stromal Cells

Cited by 138 publications

References 62 publications

Recapitulation of physiological spatiotemporal signals promotes in vitro formation of phenotypically stable human articular cartilage

Recapitulation of physiological spatiotemporal signals promotes in vitro formation of phenotypically stable human articular cartilage

MicroRNA-483-5p Modulates the Expression of Cartilage-Related Genes in Human Chondrocytes through Down-Regulating TGF-<i>β</i>1 Expression

Mimetic Hierarchical Approaches for Osteochondral Tissue Engineering

Contact Info

Product

Resources

About