Bone marrow mesenchymal stem cells (BM-MSCs) have multiple therapeutic potentials for regenerative, antiinflammatory, and immunomodulatory purposes and also show promise as vehicles for gene therapy of various metastatic cancers based on their tumor-tropic capacity. However, BM-MSCs are also a source of carcinoma-associated fibroblasts (CAFs) and may promote growth and metastasis of cancer.

Purpose Many head-and-neck cancer survivors treated with radiotherapy suffer from permanent impairment of their salivary gland function, for which few effective prevention or treatment options are available. This study explores the potential of transient activation of Wnt/β-catenin signaling in preventing radiation damage to salivary glands in a preclinical model. Methods and Materials Wnt reporter transgenic mice were exposed to 15 Gy single dose radiation in head and neck area to evaluate the effects of radiation on Wnt activity in salivary gland. Transient Wnt1 over-expression in basal epithelia was induced in inducible Wnt1 transgenic mice before, in together with, after or without local radiation, then saliva flow rate, histology, apoptosis, proliferation, stem cell activity and mRNA expression were evaluated. Results Radiation damage did not significantly affect activity of Wnt/β-catenin pathway as physical damage did. Transient expression of Wnt1 in basal epithelia significantly activated Wnt/β-catenin pathway in submandibular glands of male mice but not in those of females. Concurrent transient activation of Wnt pathway prevented chronic salivary gland dysfunction following radiation by suppressing apoptosis and preserving functional salivary stem/progenitor cells. In contrast, Wnt activation 3 days before or after irradiation did not show significant beneficial effects mainly due to failure to inhibit acute apoptosis after radiation. Excessive Wnt activation before radiation failed to inhibit apoptosis likely due to extensive induction of mitosis and up-regulation of proapoptosis gene Puma, while that after radiation might miss the critical treatment window. Conclusion These results suggest that concurrent transient activation of Wnt/β-catenin pathway could prevent radiation-induced salivary gland dysfunction.

The result revealed that the proportion of males was higher, as well as falls and MVCs were the first two main reasons, with older mean age of patients with TSCI than other countries. The occupations with highest risk for TSCI were peasants and laborers. All of these results prompted that preventive methods should be based on the characteristics of different type of patients with TSCI.

Purpose To examine effects and mechanisms of transient activation of Hedgehog pathway on rescuing radiotherapy-induced hyposalivation in head and neck cancer survivors. Experimental Design Mouse salivary glands and cultured human salivary epithelial cells were irradiated by single 15Gy dose. Hedgehog pathway was transiently activated in mouse salivary glands by shortly over-expressing Sonic hedgehog (Shh) transgene or administrating Smoothened Agonist and in human salivary epithelial cells by infecting with adenovirus encoding Gli1. Activity of Hedgehog signaling was examined by expression of Ptch1-lacZ reporter and endogenous Hedgehog target genes. Salivary flow rate was measured following pilocarpine stimulation. Salivary stem/progenitor cells (SSPCs), parasympathetic innervation and expression of related genes were examined by flow cytometry, salisphere assay, IHC, quantitative RT-PCR, Western blot and ELISA. Results Irradiation does not activate Hedgehog signaling in mouse salivary glands. Transient Shh over-expression activated Hedgehog pathway in ductal epithelia and that after irradiation rescued salivary function in male mice, which is related with preservation of functional SSPCs and parasympathetic innervation. The preservation of SSPCs was likely mediated by rescue of signaling activities of Bmi1 and Chrm1/HB-EGF pathways. The preservation of parasympathetic innervation was related with rescue of expression of neurotrophic factors such as Bdnf and Nrtn. The expression of genes related with maintenance of salivary stem/progenitor cells and parasympathetic innervation in female salivary glands and cultured human salivary epithelial cells was similarly affected by irradiation and transient Hedgehog activation. Conclusions These findings suggest that transient activation of Hedgehog pathway has the potential to restore irradiation-induced salivary gland dysfunction.

The differentiation of dental epithelia into enamel-producing ameloblasts or the root epithelial lineage compartmentalizes teeth into crowns and roots. Bmp signaling has been linked to enamel formation, but its role in root epithelial lineage differentiation is unclear. Here we show that cessation of epithelial Bmp signaling by Bmpr1a depletion during the differentiation stage switched differentiation of crown epithelia into the root lineage and led to formation of ectopic cementum-like structures. This phenotype is related to the upregulation of Wnt/␤-catenin signaling and epithelial-mesenchymal transition (EMT). Although epithelial ␤-catenin depletion during the differentiation stage also led to variable enamel defect and precocious/ectopic formation of fragmented root epithelia in some teeth, it did not cause ectopic cementogenesis and inhibited EMT in cultured dental epithelia. Concomitant epithelial ␤-catenin depletion rescued EMT and ectopic cementogenesis caused by Bmpr1a depletion. These data suggested that Bmp and Wnt/␤-catenin pathways interact antagonistically in dental epithelia to regulate the root lineage differentiation and EMT. These findings will aid in the design of new strategies to promote functional differentiation in the regeneration and tissue engineering of teeth and will provide new insights into the dynamic interactions between the Bmp and Wnt/␤-catenin pathways during cell fate decisions.

Venous thromboembolism (VTE) is the most widespread severe complication after total hip arthroplasty (THA) and total knee arthroplasty (TKA). We conducted this meta-analysis to further validate the benefits and harms of rivaroxaban use for thromboprophylaxis after THA or TKA. We thoroughly searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Trial sequential analysis (TSA) was applied to test the robustness of our findings and to obtain a more conservative estimation. Of 316 articles screened, nine studies were included. Compared with enoxaparin, rivaroxaban significantly reduced symptomatic VTE (P = 0.0001) and symptomatic deep vein thrombosis (DVT; P = 0.0001) but not symptomatic pulmonary embolism (P = 0.57). Furthermore, rivaroxaban was not associated with an increase in all-cause mortality, clinically relevant non-major bleeding and postoperative wound infection. However, the findings were accompanied by an increase in major bleeding (P = 0.02). The TSA demonstrated that the cumulative z-curve crossed the traditional boundary but not the trial sequential monitoring boundary and did not reach the required information size for major bleeding. Rivaroxaban was more beneficial than enoxaparin for preventing symptomatic DVT but increased the risk of major bleeding. According to the TSA results, more evidence is needed to verify the risk of major bleeding with rivaroxaban.

IntroductionFailed back surgery syndrome is a situation where there is failure after lumbar surgery aimed at correcting lumbar disease that is characterized by continuous back and/or leg pain. Epidural fibrosis and adhesions are among the major causes of failed back surgery syndrome. In recent years, several biomaterials have been applied as barriers or deterrents to prevent the compression of neural structures by postsurgical fibrosis.MethodsIn this study, a new bacterial cellulose (BC) anti-adhesion membrane, composed of exosomes from human umbilical cord mesenchymal stem cells, was developed. Its structure and morphology, water content, thickness, and mechanical properties of elasticity were analyzed and characterized. The degradation of the BC+exosomes (BC+Exos) membrane in vitro was evaluated, and its in vitro cytotoxicity and in vivo biocompatibility were tested. The prevention effect of BC+Exos membrane on epidural fibrosis post-laminectomy in a rabbit model was investigated.ResultsThe BC+Exos membrane showed a three-dimensional network structure constituted of high-purity cellulose and moderate mechanical properties. No degeneration was observed. The BC+Exos membrane showed no cytotoxicity and displayed biocompatibility in vivo. The BC+Exos film was able to inhibit epidural fibrosis and peridural adhesions.ConclusionBased on the current findings, the BC+Exos membrane is a promising material to prevent postoperative epidural fibrosis and adhesion.

Mesenchymal stem cells (MSCs) are important seed cells for tissue engineering and are promising targets for cell-based therapies. However, the replicative senescence of MSCs during in vitro culture limits their research and clinical applications. The molecular mechanisms underlying the replicative senescence of MSCs are not fully understood. Evidence suggests that miRNAs play important roles in replicative senescence. A microarray analysis found that the miR-29c-3p level was significantly increased during the MSC senescence process. In our study, we investigated the roles of miR-29c-3p in senescence of MSCs. We cultured MSCs for long periods of time, up and down-regulated the miR-29c-3p expression in MSCs, and examined the senescent phenotype changes. The over-expression of miR-29c-3p led to enhanced senescence-associated-β-galactosidase (SA-β-gal) staining, senescence associated secretory phenotype (SASP), senescence associated heterochromatic foci (SAHF), reduced proliferation ability, retarded osteogenic differentiation and corresponding changes in senescence markers, whereas the miR-29c-3p down-regulation had the opposite results. Dual-luciferase reporter assays demonstrated that CNOT6 is the target gene of miR-29c-3p. Knockdown of CNOT6 confirmed its inhibitory effects on the senescence of MSCs. In addition, Western blot results showed that both the p53-p21 and the p16-pRB pathways were activated during the miR-29c-3p-induced senescence of MSCs. In conclusion, our results demonstrate that miR-29c-3p promotes the senescence of MSCs by targeting CNOT6 through p53-p21 and p16-pRB pathways and highlight the contribution of post-transcriptional regulation to stem cell senescence.