Cellular hypoxia promotes osteogenic differentiation of mesenchymal stem cells and bone defect healing via STAT3 signaling

Yu, Xin; Wan, Qiang; Ye, Xiaoling; Cheng, Gu; Pathak, Janak L.; Li, Zubing

doi:10.1186/s11658-019-0191-8

Cited by 54 publications

(41 citation statements)

References 41 publications

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“…In MSC, the peak of VEGF expression occurs after 3 days of hypoxia. Hypoxia also enhanced expression and phosphorylation of STAT3 and inhibiting STAT3 reversed the VEGF induction [ 52 ]. Signal transducer and activator of transcription 3 signaling is important and necessary for endothelial cell proliferation, migration, and microvascular tube formation [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…In transgenic mice, specific inactivation of STAT3 in osteoblasts and osteocytes decreased mechanical load-driven bone formation [ 55 ]. CoCl 2 , a mimic of hypoxia, enhanced migration in MSCs and promoted osteogenic differentiation of MSCs and bone defect healing via STAT3 phosphorylation upregulation [ 28 , 52 ]. An increase in STAT3 phosphorylation was also observed during differentiation of human osteoprogenitors.…”

Section: Discussionmentioning

confidence: 99%

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Platelet Lysate Induces in Human Osteoblasts Resumption of Cell Proliferation and Activation of Pathways Relevant for Revascularization and Regeneration of Damaged Bone

Nguyen

Nardini

Ruggiu

et al. 2020

IJMS

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To understand the regenerative effect of platelet-released molecules in bone repair one should investigate the cascade of events involving the resident osteoblast population during the reconstructive process. Here the in vitro response of human osteoblasts to a platelet lysate (PL) stimulus is reported. Quiescent or very slow dividing osteoblasts showed a burst of proliferation after PL stimulation and returned to a none or very slow dividing condition when the PL was removed. PL stimulated osteoblasts maintained a differentiation capability in vitro and in vivo when tested in absence of PL. Since angiogenesis plays a crucial role in the bone healing process, we investigated in PL stimulated osteoblasts the activation of hypoxia-inducible factor 1-alpha (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) pathways, involved in both angiogenesis and bone regeneration. We observed phosphorylation of STAT3 and a strong induction, nuclear translocation and DNA binding of HIF-1α. In agreement with the induction of HIF-1α an enhanced secretion of vascular endothelial growth factor (VEGF) occurred. The double effect of the PL on quiescent osteoblasts, i.e., resumption of proliferation and activation of pathways promoting both angiogenesis and bone formation, provides a rationale to the application of PL as therapeutic agent in post-traumatic bone repair.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Platelet Lysate Induces in Human Osteoblasts Resumption of Cell Proliferation and Activation of Pathways Relevant for Revascularization and Regeneration of Damaged Bone

Nguyen

Nardini

Ruggiu

et al. 2020

IJMS

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“…In mice, both MSCs and the media from bone marrow-derived MSCs cultured under hypoxic conditions demonstrated increased amounts of basic fibroblast growth factor (bFGF), vascular endothelial growth factor A (VEGF-A), interleukin 6 (IL-6), and interleukin 8 (IL-8), and enhanced the proliferation and migration of endothelial cells and other cells including macrophages (Chen et al, 2014 ). Osteogenesis and angiogenesis are also controlled by the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3), an important regulator of bone homeostasis (Yu et al, 2019 ). Using murine MSCs in vitro and a femoral defect model, hypoxia was shown to upregulate the phosphorylation of STAT and was important to the healing of a bone defect.…”

Section: Methods To Enhance the Function Of Harvested Cells ( mentioning

confidence: 99%

“…Using murine MSCs in vitro and a femoral defect model, hypoxia was shown to upregulate the phosphorylation of STAT and was important to the healing of a bone defect. Interestingly, the duration of hypoxia was critical to osteogenesis and angiogenesis, with 3 days of exposure being optimal (Yu et al, 2019 ). Other studies in animals have confirmed hypoxic preconditioning as a method to enhance osteogenesis, angiogenesis and bone healing, even in aged animals (Fan et al, 2015 ; Zhang et al, 2018 ).…”

Section: Methods To Enhance the Function Of Harvested Cells ( mentioning

confidence: 99%

Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches

Goodman

Lin

2020

Front. Bioeng. Biotechnol.

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Healing of fractures and bone defects normally follows an orderly series of events including formation of a hematoma and an initial stage of inflammation, development of soft callus, formation of hard callus, and finally the stage of bone remodeling. In cases of severe musculoskeletal injury due to trauma, infection, irradiation and other adverse stimuli, deficient healing may lead to delayed or non-union; this results in a residual bone defect with instability, pain and loss of function. Modern methods of mechanical stabilization and autologous bone grafting are often successful in achieving fracture union and healing of bone defects; however, in some cases, this treatment is unsuccessful because of inadequate biological factors. Specifically, the systemic and local microenvironment may not be conducive to bone healing because of a loss of the progenitor cell population for bone and vascular lineage cells. Autologous bone grafting can provide the necessary scaffold, progenitor and differentiated lineage cells, and biological cues for bone reconstruction, however, autologous bone graft may be limited in quantity or quality. These unfavorable circumstances are magnified in systemic conditions with chronic inflammation, including obesity, diabetes, chronic renal disease, aging and others. Recently, strategies have been devised to both mitigate the necessity for, and complications from, open procedures for harvesting of autologous bone by using minimally invasive aspiration techniques and concentration of iliac crest bone cells, followed by local injection into the defect site. More elaborate strategies (not yet approved by the U.S. Food and Drug Administration-FDA) include isolation and expansion of subpopulations of the harvested cells, preconditioning of these cells or inserting specific genes to modulate or facilitate bone healing. We review the literature pertinent to the subject of modifying autologous harvested cells including MSCs to facilitate bone healing. Although many of these techniques and technologies are still in the preclinical stage and not yet approved for use in humans by the FDA, novel approaches to accelerate bone healing by modifying cells has great potential to mitigate the physical, economic and social burden of non-healing fractures and bone defects.

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“…Odontogenesis was determined by cellular accumulation of alizarin red-stained mineralized matrix. The mineralized matrix in different culture conditions was quantified as described previously (Yu et al, 2019).…”

Section: In Vitro Matrix Mineralization Assaymentioning

confidence: 99%

Mesoporous Bioactive Glass Nanoparticles Promote Odontogenesis and Neutralize Pathophysiological Acidic pH

et al. 2020

Self Cite

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Pathophysiological acidic-pH hinders the dental biomaterial-based pulp-dentin regeneration. Bioactive glass (BG) synthesized by sol-gel methods had shown odontogenic and pulp regeneration potential. However, the pathophysiological acidic-pH neutralizing potential of BG has not been tested yet. In this study, we aimed to design mesoporous BG-nanoparticles by a well-established sol-gel method and test its odontogenic and acidic-pH neutralizing potential. BG-nanoparticles were synthesized and further characterized by SEM, EDS, XRD, and FTIR. Mono-dispersed and spherical mesoporous BG-nanoparticles with size 300-500 nm were successfully fabricated. Effect of BG ionic extraction in DMEM with 0.1-2.5 g/L BG concentrations on proliferation and odontogenic differentiation of stem cells from human exfoliated deciduous teeth (SHED) was analyzed. All the BG ionic extractions did not affect SHEDs proliferation at early time points (day 1 and 3). BG ionic extraction 0.5 g/L robustly enhanced odontogenic differentiation of SHEDs, as shown by the expression pattern of ALP, Col1, DSPP, and matrix mineralization results. The chemical composition of the BG ionic extraction-induced mineralized matrix resembled natural dentin. BGnanoparticles/alginate paste neutralized the butyric acid solution (pH 5.4) and buffered within pH 8.3 for a month. Our findings showed the odontogenic and pathophysiological acidic-pH neutralizing potential of BG-nanoparticles, indicating its possible application in pulp-dentin regeneration under pathophysiologically challenged acidic environment.

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Cellular hypoxia promotes osteogenic differentiation of mesenchymal stem cells and bone defect healing via STAT3 signaling

Cited by 54 publications

References 41 publications

Platelet Lysate Induces in Human Osteoblasts Resumption of Cell Proliferation and Activation of Pathways Relevant for Revascularization and Regeneration of Damaged Bone

Platelet Lysate Induces in Human Osteoblasts Resumption of Cell Proliferation and Activation of Pathways Relevant for Revascularization and Regeneration of Damaged Bone

Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches

Mesoporous Bioactive Glass Nanoparticles Promote Odontogenesis and Neutralize Pathophysiological Acidic pH

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