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

2019 ◽  
Vol 24 (1) ◽  
Author(s):  
Xin Yu ◽  
Qilong Wan ◽  
Xiaoling Ye ◽  
Yuet Cheng ◽  
Janak L. Pathak ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Bone Defect ◽  
Precursor Cells ◽  
Defect Healing ◽  
Stat3 Signaling ◽  
Bone Defect Healing ◽  
Cellular Hypoxia

Abstract Background Hypoxia in the vicinity of bone defects triggers the osteogenic differentiation of precursor cells and promotes healing. The activation of STAT3 signaling in mesenchymal stem cells (MSCs) has similarly been reported to mediate bone regeneration. However, the interaction between hypoxia and STAT3 signaling in the osteogenic differentiation of precursor cells during bone defect healing is still unknown. Methods In this study, we assessed the impact of different durations of CoCl2-induced cellular hypoxia on the osteogenic differentiation of MSCs. Role of STAT3 signaling on hypoxia induced osteogenic differentiation was analyzed both in vitro and in vivo. The interaction between cellular hypoxia and STAT3 signaling in vivo was investigated in a mouse femoral bone defect model. Results The peak osteogenic differentiation and expression of vascular endothelial growth factor (VEGF) occurred after 3 days of hypoxia. Inhibiting STAT3 reversed this effect. Hypoxia enhanced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and STAT3 phosphorylation in MSCs. Histology and μ-CT results showed that CoCl2 treatment enhanced bone defect healing. Inhibiting STAT3 reduced this effect. Immunohistochemistry results showed that CoCl2 treatment enhanced Hif-1α, ALP and pSTAT3 expression in cells present in the bone defect area and that inhibiting STAT3 reduced this effect. Conclusions The in vitro study revealed that the duration of hypoxia is crucial for osteogenic differentiation of precursor cells. The results from both the in vitro and in vivo studies show the role of STAT3 signaling in hypoxia-induced osteogenic differentiation of precursor cells and bone defect healing.

Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing

2018 ◽  
Vol 399 (11) ◽  
pp. 1313-1323 ◽  
Author(s):  
Xin Yu ◽  
Zhi Li ◽  
Qilong Wan ◽  
Xin Cheng ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Osteogenic Differentiation ◽  
Bone Defect ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Defect Healing ◽  
Stat3 Signaling ◽  
Bone Defect Healing

Abstract Mesenchymal stem cells (MSCs) undergo osteogenic differentiation during bone defect healing. However, the role of JAK2/STAT3 in the osteogenic differentiation of MSCs and bone defect healing is still not fully understood. In this study, we aimed to analyze the effect of AG490, a JAK2-specific inhibitor, on MSCs proliferation and osteogenic differentiation as well as in bone defect healing. We used AG490 to inhibit the JAK2/STAT3 signaling in a mice bone marrow stromal cells (BMSCs) culture. AG490 inhibited BMSCs proliferation and osteogenic differentiation markers, i.e. Col1α, Alp and Ocn expression in mRNA and protein levels. Inhibition of JAK2 reduced ALP activity and matrix mineralization in BMSCs culture. Inhibition of JAK2 reduced phosphorylation of STAT3, AKT, P38, and JNK phosphorylation. Immunohistochemistry showed high numbers of pJAK2, pSTAT3 and ALP positive cells and AG490 reduced this effect in vivo. Histology and μ-computed tomography (CT) data showed that AG490 treatment inhibits bone regeneration and bone defect healing. Our results clearly showed the inhibitory effect of AG490 on proliferation and osteogenic differentiation of BMSCs, bone regeneration and bone defect healing. Moreover, AG490 inhibited phosphorylation of STAT3, P38, JNK and AKT. This suggests the possible role of JAK2/STAT3 signaling in hypoxia-induced osteogenic differentiation of MSCs and bone defect healing.

scholarly journals In vitro and in vivo assessment of nanostructured porous biphasic calcium phosphate ceramics for promoting osteogenesis in an osteoporotic environment

RSC Advances ◽  
2018 ◽  
Vol 8 (26) ◽  
pp. 14646-14653 ◽  
Author(s):  
Kun Zhang ◽  
Jieyu Zhang ◽  
Kelei Chen ◽  
Xuefeng Hu ◽  
Yunbing Wang ◽  
...  
Keyword(s):  
Calcium Phosphate ◽  
Bone Defect ◽  
Biphasic Calcium Phosphate ◽  
Calcium Phosphate Ceramics ◽  
Defect Healing ◽  
Bone Defect Healing ◽  
In Vivo Assessment ◽  
Porous Biphasic Calcium Phosphate

Nanostructured porous biphasic calcium phosphate ceramics are able to significantly promote bone defect healing in an osteoporotic environment.

Transplantation of copper-doped calcium polyphosphate scaffolds combined with copper (II) preconditioned bone marrow mesenchymal stem cells for bone defect repair

2018 ◽  
Vol 32 (6) ◽  
pp. 738-753 ◽  
Author(s):  
Yanhong Li ◽  
Jing Wang ◽  
Yuliang Wang ◽  
Wenjia Du ◽  
Shuanke Wang
Keyword(s):  
Bone Defect ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Defect Healing ◽  
Calcium Polyphosphate ◽  
Bone Defect Healing ◽  
Marrow Mesenchymal Stem Cells ◽  
Osteogenic Factors

Calcium polyphosphate is a bioactive ceramic that possesses similar mineral components to bone and possess good physicochemical properties. However, pure calcium polyphosphate scaffold is brittle, and it is insufficient in promoting vascularization and osteoinductivity. This study was conducted to assess whether copper (Cu) incorporated into calcium polyphosphate could improve the scaffolds’ inherent shortcomings. In the experiments, Cu-calcium polyphosphate scaffolds’ mechanical strength, biocompatibility, and biodegradability were researched primarily. And then, hypoxia-inducible factor 1-alpha expression along with angiogenesis and osteogenesis potential when the scaffolds treated with the bone marrow mesenchymal stem cells (BMMSCs) were analyzed in vitro. In in vivo studies, the Cu-calcium polyphosphate scaffolds combined with the liquid extract preconditioned BMMSCs were implanted into animal model to repair the bone defects. Meanwhile, we also evaluate the expression of angiogenic and osteogenic factors. For comparison, Cu-calcium polyphosphate, calcium polyphosphate, and blank control groups were designed. According to the results, proper content of Cu incorporated with calcium polyphosphate (0.1% Cu-calcium polyphosphate) did not significantly change the scaffold’s degradation velocity, but it obtained higher compress mechanical strength and Cu-doped scaffolds were less brittle. Besides, these scaffolds incorporated with Cu showed better cytocompatibility and cell proliferation activity. Moreover, after Cu was doped, the hypoxia-inducible factor 1-alpha expression was up-regulated with the angiogenic and osteogenic factors levels increased both in in vitro and in vivo study. The bone defect healing capacity was accessed, using Cu-calcium polyphosphate combined with preconditioned BMMSCs further enhanced new bone formation and improved hypoxia-inducible factor 1-alpha, alkaline phosphatase, osteocalcin, and vascular endothelial growth factor expression. In conclusion, doped Cu into calcium polyphosphate was an alternative strategy for improving calcium polyphosphate’s mechanical property and promoting the osteogenesis and angiogenesis potential. Using Cu-calcium polyphosphate scaffolds combined with Cu preconditioned BMMSCs to treat bone defect could enhance bone defect healing.

scholarly journals Osteoclast-Derived Extracellular miR-106a-5p Promotes Osteogenic Differentiation and Facilitates Bone Defect Healing

2021 ◽  
Author(s):  
Yutong Wu ◽  
Hongbo Ai ◽  
Yuchi Zou ◽  
Jianzhong Xu
Keyword(s):  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Signal Molecules ◽  
Calvarial Defect ◽  
Communication Mode ◽  
Defect Healing ◽  
Bone Defect Healing ◽  
Intercellular Communications

Abstract Small extracellular vesicles (sEVs) are considered to play critical roles in intercellular communications during normal and pathological processes since they are enriched with miRNAs and other signal molecules. In bone remodeling, osteoclasts generate large amounts of sEVs. However, there is very little research about whether and how osteoclast-derived sEVs (OC-sEVs) affect surrounding cells. In our study, microarray analysis identified miR-106a-5p highly enriched in OC-sEV. Further experiments confirmed that OC-sEVs inhibited Fam134a through miR-106a-5p and significantly promoted bone mesenchymal stem cell (BMSC) osteogenic mineralization in vitro. Next, we prepared sEV-modified demineralized bone matrix (DBM) as a repair scaffold, and used a calvarial defect mouse model to evaluate the pro-osteogenic activities of the scaffold. In vivo result indicated DBM modified with miR-106a-5p-sEVs showed an enhanced capacity of bone regeneration. This important finding further emphasizes that sEV-mediated miR-106a-5p transfer play critical roles in osteogenesis and indicate a novel communication mode between osteoclasts and BMSCs.

scholarly journals Augmentation of bone defect healing using a new biocomposite scaffold: An in vivo study in sheep

2010 ◽  
Vol 6 (9) ◽  
pp. 3755-3762 ◽  
Author(s):  
U. van der Pol ◽  
L. Mathieu ◽  
S. Zeiter ◽  
P.-E. Bourban ◽  
P.-Y. Zambelli ◽  
...  
Keyword(s):  
Bone Defect ◽  
In Vivo Study ◽  
Defect Healing ◽  
Bone Defect Healing

scholarly journals L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Marco Giordano ◽  
Alessandra Decio ◽  
Chiara Battistini ◽  
Micol Baronio ◽  
Fabrizio Bianchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Tumor Formation ◽  
In Vitro Assays ◽  
Tumor Initiation ◽  
Loss Of Function ◽  
Stat3 Signaling

Abstract Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. Methods The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. Results We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. Conclusions Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

scholarly journals Time kinetics of bone defect healing in response to BMP-2 and GDF-5 characterised by in vivo biomechanics

2011 ◽  
Vol 21 ◽  
pp. 177-192 ◽  
Author(s):  
D Wulsten ◽  
◽  
V Glatt ◽  
A Ellinghaus ◽  
K Schmidt-Ble ◽  
...  
Keyword(s):  
Bone Defect ◽  
Defect Healing ◽  
Bone Defect Healing ◽  
Kinetics Of
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