Hypoxia Enhances Chondrogenesis and Prevents Terminal Differentiation through PI3K/Akt/FoxO Dependent Anti-Apoptotic Effect

Lee, Hsieh Hsing; Chang, Chia Chi; Shieh, Ming Jium; Wang, Jung Pan; Chen, Yi Te; Young, Tai Horng; Hung, Shih Chieh

doi:10.1038/srep02683

Cited by 118 publications

(102 citation statements)

References 46 publications

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“…However, the determination of cell fate is typically a multistage decision involving multiple signaling pathways in a spatiotemporal manner. In addition to single candidates, it is likely that multiple signaling pathways are able to act in concert or even synergistically (21). The involvement of multiple signaling pathways upon exposure to distinct oxygen tension is also suggested by observations in our current study.…”

Section: Discussionsupporting

confidence: 64%

“…Moreover, this pathway is associated with both chondrogenesis and the induction of hypertrophic differentiation in articular cartilage during the pathological development of osteoarthritis (20). Alternatively, it has recently been reported that the activity of the PI3K/AKT/FOXO pathway is influenced by oxygen tension and is able to enhance chondrogenesis, inhibit hypertrophic differentiation, and prevent endochondral ossification (21). Also, SMAD signaling induced by members of the TGF-β/BMP family of growth factors is influenced by oxygen tension (22).…”

Section: Discussionmentioning

confidence: 99%

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Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate

Leijten¹,

Georgi²,

Teixeira³

et al. 2014

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

112

114

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Actively steering the chondrogenic differentiation of mesenchymal stromal cells (MSCs) into either permanent cartilage or hypertrophic cartilage destined to be replaced by bone has not yet been possible. During limb development, the developing long bone is exposed to a concentration gradient of oxygen, with lower oxygen tension in the region destined to become articular cartilage and higher oxygen tension in transient hypertrophic cartilage. Here, we prove that metabolic programming of MSCs by oxygen tension directs chondrogenesis into either permanent or transient hyaline cartilage. Human MSCs chondrogenically differentiated in vitro under hypoxia (2.5% O 2 ) produced more hyaline cartilage, which expressed typical articular cartilage biomarkers, including established inhibitors of hypertrophic differentiation. In contrast, normoxia (21% O 2 ) prevented the expression of these inhibitors and was associated with increased hypertrophic differentiation. Interestingly, gene network analysis revealed that oxygen tension resulted in metabolic programming of the MSCs directing chondrogenesis into articular-or epiphyseal cartilage-like tissue. This differentiation program resembled the embryological development of these distinct types of hyaline cartilage. Remarkably, the distinct cartilage phenotypes were preserved upon implantation in mice. Hypoxia-preconditioned implants remained cartilaginous, whereas normoxia-preconditioned implants readily underwent calcification, vascular invasion, and subsequent endochondral ossification. In conclusion, metabolic programming of MSCs by oxygen tension provides a simple yet effective mechanism by which to direct the chondrogenic differentiation program into either permanent articular-like cartilage or hypertrophic cartilage that is destined to become endochondral bone.tissue engineering | chondral defects | skeletogenesis | cell therapy | regenerative medicine

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate

Leijten¹,

Georgi²,

Teixeira³

et al. 2014

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

112

114

View full text Add to dashboard Cite

show abstract

“…Hypoxia was shown to enhance chondrogenic differentiation of MSCs [424] and chondrocytes [425]. Following these findings, it is reasonable to hypothesize that the application of mechanical loading under hypoxic conditions further enhances chondrogenic differentiation and maturation of tissue engineered cartilage constructs.…”

Section: Future Directionsmentioning

confidence: 89%

Hydrogels and bioreactors for cartilage research and functional tissue engineering

Meinert¹

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“…Hypoxia was suggested to promote chondrogenesis in rat MSCs [194] and human MSCs [195]. Thus we investigated the effect of hypoxia on hMSC chondrogensis in our system with pathway inhibitors.…”

Section: Hypoxiamentioning

confidence: 99%

“…MSCs [195]. Treatment with basic fibroblast growth factor (FGF-2) during MSC expansion could inhibit the differentiation of MSCs [196,197].…”

Section: Culture Conditions Of Mscs During Expansion and Differentiationmentioning

confidence: 99%

Technique and method development for intervertebral disc (IVD) research

Lee¹,

李芷恩²

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Intervertebral disc (IVD) degeneration is one of the major causes of low back pain. The direct and indirect cost of managing back pain posts heavy socioeconomic burden to the society. Improved technologies and techniques together with well documented experiments will benefit the research field by saving effort in doing the optimization in every laboratory and avoiding experiment failure due to incomplete understanding of the procedures. These can accelerate scientific discovery, reduce the sacrifice of animals and enable a more effective use of funding.Nucleus pulposus (NP) is the central part of IVD. Differences in matrix compositions in human NP clinical samples demand different cell isolation protocols for optimal results but there is no clear guide about this to date. Sub-optimal protocols may result in low cell yield, limited reliability of results or even failure of experiments. We experimented different isolation protocols to study different parameters involved and suggested some rules for cell isolation in three main applications: RNA extraction for phenotyping, cell isolation for cell culture, and characterization by flow cytometry.In addition, instead of extracting RNA from isolated cells, extraction of RNA from tissues directly may avoid the change of RNA levels during the cell isolation process.However, extraction of RNA directly from human and large animal IVD tissue is technically challenging due to its tough nature, low cell-to-matrix ratio and high proteoglycan content. Thus we developed a method for RNA extraction from bovine disc tissues by integrating the use of cryosectioning, additional phase separation and high salt precipitation into conventional guanidinium thiocyanate based method. With this method, RNA could be extracted from the NP tissue directly but the concentration was low. A shift toward 270 nm was observed in its UV spectrum which was due to phenol contamination. This caused an overestimation of RNA concentration. Hence we developed a computational method based on UV spectra for correcting the In short, different methods related to IVD research were developed and optimized. With improved methods together with a better understanding of the underlying rationale, researchers can save time and cost in their experiments and reduce experiment failure rate. This will help to accelerate researches. New methods also enable studies which were not feasible in the past.(484 words)

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Hypoxia Enhances Chondrogenesis and Prevents Terminal Differentiation through PI3K/Akt/FoxO Dependent Anti-Apoptotic Effect

Cited by 118 publications

References 46 publications

Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate

Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate

Hydrogels and bioreactors for cartilage research and functional tissue engineering

Technique and method development for intervertebral disc (IVD) research

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