Oxygen tension regulates the osteogenic, chondrogenic and endochondral phenotype of bone marrow derived mesenchymal stem cells

Sheehy, Eamon J.; Buckley, Conor T.; Kelly, Daniel J.

doi:10.1016/j.bbrc.2011.11.105

Cited by 125 publications

(132 citation statements)

References 28 publications

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“…Previous studies have suggested that the development of a low oxygen micro-environment within core regions of MSC-seeded hydrogels will suppress hypertrophy and calcification in this region of the engineered tissue [31]. In the context of MSC seeded fibrin gels, it may be that the combination of a spread cell shape and such low oxygen conditions are supporting a sub-population of MSCs undergoing direct osteoblastic differentiation in response to the β-GP (an osteogenic inducer) within the hypertrophic medium, as previous studies have demonstrated enhanced calcium deposition by MSCs at an oxygen tension of 5% pO2 compared to 20% pO2 [30,36]. Previous studies have also demonstrated that MSCs cultured in a chondrogenic medium containing β-GP accumulated more calcium in hypoxic conditions than in normoxic conditions when seeded onto an electrospun fibrous polymer scaffold [37], a scaffold which also promotes an elongated morphology in MSCs [38].…”

Section: Micro-computed Tomographymentioning

confidence: 94%

“…Bone marrow derived MSCs were isolated from the femoral shaft of 4 month old pigs and expanded according to a modified method for human MSCs [30] in high glucose Dulbecco's modified eagle's medium GlutaMAX (hgDMEM) supplemented with 10% v/v foetal bovine serum (FBS), 100 U/mL penicillin -100 µg/mL streptomycin (all Gibco, Biosciences, Dublin Ireland) and 2.5 µg/mL amphotericin B (Sigma-Aldrich, Dublin, Ireland) at 20% pO 2 .…”

Section: Isolation and Expansion Of Mscsmentioning

confidence: 99%

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Engineering cartilage or endochondral bone: A comparison of different naturally derived hydrogels

et al. 2015

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Cartilaginous tissues engineered using mesenchymal stem cells (MSCs) have been shown to generate bone in vivo by executing an endochondral program. This may hinder the use of MSCs for articular cartilage regeneration, but opens the possibility of using engineered cartilaginous tissues for large bone defect repair. Hydrogels may be an attractive tool in the scaling-up of such tissue engineered grafts for endochondral bone regeneration. In this study, we compared the capacity of different naturally derived hydrogels (alginate, chitosan, and fibrin) to support chondrogenesis and hypertrophy of MSCs in vitro and endochondral ossification in vivo. In vitro, alginate and chitosan constructs accumulated the highest levels of sGAG, with chitosan constructs synthesising the highest levels of collagen. Alginate and fibrin constructs supported the greatest degree of calcium accumulation, though only fibrin constructs calcified homogenously. In vivo, chitosan constructs facilitated neither vascularization nor endochondral ossification, and also retained the greatest amount of sGAG, suggesting it to be a more suitable material for the engineering of articular cartilage.Both alginate and fibrin constructs facilitated vascularization and endochondral bone formation as well as the development of a bone marrow environment. Alginate constructs accumulated significantly more mineral and supported greater bone formation in central regions of the engineered tissue. In conclusion, this study demonstrates the capacity of chitosan hydrogels to promote and better maintain a chondrogenic phenotype in MSCs and highlights the potential of utilizing alginate hydrogels for MSC-based endochondral bone tissue engineering applications.

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Section: Micro-computed Tomographymentioning

confidence: 94%

Section: Isolation and Expansion Of Mscsmentioning

confidence: 99%

Engineering cartilage or endochondral bone: A comparison of different naturally derived hydrogels

et al. 2015

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“…The initialisation step began when the newly differentiated CCs transformed into HCs. Based on the literature, this was assumed to occur when the local oxygen tension increased beyond a threshold value (O 2 hypertrophy ) (Sheehy et al, 2012;Leijten et al, 2014). The ossification step then characterised the process by which the newly transformed HCs recruit blood vessels and osteoprogenitor cells before undergoing apoptosis (Mackie et al 2008) or transdifferentiating into OBs (Bahney et al, 2014).…”

Section: Msc Differentiation and Hypertrophymentioning

confidence: 99%

“…This computational model did not however propose a specific hypothesis for how environmental factors regulate the initiation and progression of chondrocyte hypertrophy and endochondral ossification, which is central to successful secondary fracture healing. This is clearly a potential limitation of such models, as a number of recent studies have demonstrated that low oxygen conditions can supress hypertrophy and endochondral ossification of chondrogenically primed MSCs (Zhu et al, 2014;Sheehy et al, 2012;Gawlitta et al, 2012;Leijten et al, 2012Leijten et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

“…Motivated by in-vitro observations (Zhu et al, 2014;Sheehy et al, 2012;Gawlitta et al, 2012;Leijten et al, 2012Leijten et al, , 2014 our previous in-silico model of MSC differentiation (Burke and Kelly, 2012) was updated to include specific rules for how oxygen levels regulate hypertrophy of chondrocytes. The model was then tested by attempting to simulate fracture healing within a murine tibia in both normal and ischemic limbs, where experimental data was generated to quantify the proportion of hypertrophic cartilage within the calluses of such bones at specific time-points after the initiation of injury.…”

Section: Introductionmentioning

confidence: 99%

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A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

O'Reilly

Hankenson

Kelly

2016

Biomech Model Mechanobiol

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While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by the local oxygen tension and substrate stiffness. This was updated to include conditions for oxygen regu- lated cell death and endochondral ossification. The updated algorithm was validated by using it within a model of normal fracture healing where it predicted the experimentally observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post fracture (dpf). Furthermore, it also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment the model predicted the experimentally observed reduction in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe angiogenic impairment predicted the development of fibrous and necrotic tissue within the callus. These results provide insight into how environmental factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that endochondral ossification during fracture healing is governed by the local oxygen tension.

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Spatiotemporalized Hydrogel Microspheres Promote Vascularized Osteogenesis via Ultrasound Oxygen Delivery

Chen,

Han,

Cao

et al. 2023

Adv Funct Materials

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Disturbance of spatiotemporal oxygen balance is the main cause of delayed healing or nonhealing of large bone defects. The accurate administration of oxygen to regulate disruptions in the spatiotemporal oxygen equilibrium during 9 h of hypoxia is imperative for bone tissue regeneration. Herein, oxygen‐loaded nanobubbles prepared by double emulsification are successfully embedded in GelMA/HepMA microsphere macromolecular meshwork by microfluidic techniques, and a spatiotemporalized hydrogel microsphere is constructed by noncovalently binding bone morphogenetic protein 2 (BMP‐2). The spatiotemporalized hydrogel microspheres precisely “remote control” oxygen release by ultrasound in vitro 9 h after bone injury to regulate spatiotemporal oxygen homeostasis disorder, maintain a high level of vascular endothelial growth factor (VEGF) expression, and accelerate bone repair. The spatiotemporalized hydrogel microspheres possess good oxygen‐carrying capacity and ultrasonic responsiveness, and the oxygen concentration increases to 1.63, 1.95, 2.11, and 2.29 times under the ultrasound action at different intensities of 1, 2, 3, and 4 W, respectively, providing the conditions for the precise regulation of spatiotemporal oxygen balance disorder by ultrasound. In the in vitro hypoxia model and in vivo rat femoral defect model, the spatiotemporal hydrogel microspheres show good vascularization and osteogenesis capabilities, which provide a new strategy for the clinical treatment of large bone defects.

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Oxygen tension regulates the osteogenic, chondrogenic and endochondral phenotype of bone marrow derived mesenchymal stem cells

Cited by 125 publications

References 28 publications

Engineering cartilage or endochondral bone: A comparison of different naturally derived hydrogels

Engineering cartilage or endochondral bone: A comparison of different naturally derived hydrogels

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

Spatiotemporalized Hydrogel Microspheres Promote Vascularized Osteogenesis via Ultrasound Oxygen Delivery

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