PAFR/Stat3 axis maintains the symbiotic ecosystem between tumor and stroma to facilitate tumor malignancy

Stroma surrounding the tumor cells plays crucial roles for tumor progression. However, little is known about the factors that maintain the symbiosis between stroma and tumor cells. In this study, we found that the transcriptional regulator-signal transducer and activator of transcription 3 (Stat3) was frequently activated in cancer-associated fibroblasts (CAFs), which was a potent facilitator of tumor malignancy, and formed forward feedback loop with platelet-activating factor receptor (PAFR) both in CAFs and tumor cells. Importantly, PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells. Two central Stat3-related cytokine signaling molecules-interleukin 6 (IL-6) and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs. Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model. Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.

Selection and application of biodegradable scaffold in tracheal tissue engineering / 国际生物医学工程杂志

Long tracheal lesions are mainly caused by stenosis, infection, trauma, malignant tumors and other factors. Resection of the diseased tissue or stenosis and end-to-end anastomosis is currently the gold standard for long tracheal lesions treatment. However, these treatment programs have proven to have major limitations. In recent years, tissue engineering technology has been regarded as a promising medical alternative treatment method, and the selection of scaffold materials is one of key parts. With the continuous exploration of domestic and foreign researchers, biological materials have been continuously developed and applied to the research of tissue engineering trachea. Tissue engineering degradable scaffold materials can be divided into natural polymer material scaffolds and synthetic polymer scaffolds according to the different sources. The scaffold material can be modified or compounded as needed to improve the biological properties of scaffolds. In addition, with the continuous development of biological printing technology, different scaffold materials can be better combined and used. Biodegradable scaffolds have become a new research direction in the field of tissue engineering trachea due to their polymer properties, and have good application prospects.

Genipin cross-linked decellularized scaffold for allogenic transplantation in situ / 国际生物医学工程杂志

Objective@#To explored the bio-compatibility and cartilage regeneration of the rabbits genipin cross-linked decellularized scaffold, to provide experimental and theoretical support for the clinical application of genipin cross-linked decellularized scaffold.@*Methods@#Detergent-enzyme method was used to prepare decellularized tracheal scaffolds. Cellular content of native trachea and decellularized trachea were compared by 4′, 6-diamidino-2-phenylindole(DAPI) staining. Masson trichrome staining was used to compare the histological structure of the progenitor tube, decellularized trachea, and genipin cross-linked decellularized trachea. Nine adult New Zealand white rabbits were randomly divided into autologous tracheal transplantation group (negative control group), allogeneic tracheal transplantation group (positive control group), and genipin cross-linked decellularized tracheal transplantation group (experimental group). Autologous bone marrow mesenchymal stem cells were implanted on the surface of trachea in each group. The blood cells and type II collagen were detected to compare the inflammatory response and chondrocyte regeneration after tracheal orthotopic transplantation in the three groups.@*Results@#After DAPI staining and light microscope observation (×200), the cell content of the acellular 7-cycle trachea [(143.0 ± 71.1) cells/field] was significantly lower than that of the native trachea [(853.5 ± 149.6) cells/field], and the difference was statistically significant (P<0.001). Masson′s trichrome staining showed that the tissue structure of genipin cross-linked decellularized trachea was more complete. Blood cell analysis and type II collagen test results showed that genipin cross-linked decellularized trachea transplanted with bone marrow mesenchymal stem cells after transplantation in situ has little rejection and can be converted into chondrocytes by the action of related growth factors in vivo.@*Conclusions@#Genipin cross-linked decellularized tracheal scaffold combined with stem cell transplantation can successfully construct a tracheal in situ replacement model. This study provides a strong support for the research of tissue engineering trachea.

A Comparative Study of the Effects of Different Decellularization Methods and Genipin-Cross-Linking on the Properties of Tracheal Matrices

BACKGROUND: Different decellularization methods can affect the integrity and the biomechanical and biocompatible properties of the tracheal matrix. Natural cross-linking with genipin can be applied to improve those properties. The goals of this study were to evaluate the effects of different decellularization methods on the properties of genipin-cross-linked decellularized tracheal matrices in rabbits. METHODS: The tracheas of New Zealand rabbits were decellularized by the Triton-X 100-processed method (TPM) and the detergent-enzymatic method (DEM) and were then cross-linked with genipin. Mechanical tests, haematoxylin-eosin staining, Masson trichrome staining, Safranin O staining, DAPI staining, scanning electronic microscopy (SEM), and biocompatibility tests were used to evaluate the treatment. The bioengineered trachea and control trachea were then implanted into allogeneic rabbits for 30 days. The structural and functional analyses were performed after transplantation. RESULTS: The biomechanical tests demonstrated that the biomechanical properties of the decellularized tracheas decreased and that genipin improved them (p < 0.05). The histological staining results revealed that most of the mucosal epithelial cells were removed and that the decellularized trachea had lower immunogenicity than the control group. The analysis of SEM revealed that the decellularized trachea retained the micro- and ultra-structural architectures of the trachea and that the matrices cross-linked with genipin were denser. The biocompatibility evaluation and in vivo implantation experiments showed that the decellularized trachea treated with the DEM had better biocompatibility than that treated with the TPM and that immunogenicity in the cross-linked tissues was lower than that in the uncross-linked tissues (p < 0.05). CONCLUSION: Compared with the trachea treated with the TPM, the rabbit trachea processed by the DEM had better biocompatibility and lower immunogenicity, and its structural and mechanical characteristics were effectively improved after the genipin treatment, which is suitable for engineering replacement tracheal tissue.

Genipin cross-linked decellularized scaffold for allogenic transplantation in situ / 国际生物医学工程杂志

Objective To explored the bio-compatibility and cartilage regeneration of the rabbits genipin cross-linked decellularized scaffold, to provide experimental and theoretical support for the clinical application of genipin cross-linked decellularized scaffold. Methods Detergent-enzyme method was used to prepare decellularized tracheal scaffolds. Cellular content of native trachea and decellularized trachea were compared by 4', 6-diamidino-2-phenylindole(DAPI) staining. Masson trichrome staining was used to compare the histological structure of the progenitor tube, decellularized trachea, and genipin cross-linked decellularized trachea. Nine adult New Zealand white rabbits were randomly divided into autologous tracheal transplantation group (negative control group), allogeneic tracheal transplantation group (positive control group), and genipin cross-linked decellularized tracheal transplantation group (experimental group). Autologous bone marrow mesenchymal stem cells were implanted on the surface of trachea in each group. The blood cells and type II collagen were detected to compare the inflammatory response and chondrocyte regeneration after tracheal orthotopic transplantation in the three groups. Results After DAPI staining and light microscope observation (×200), the cell content of the acellular 7-cycle trachea [(143.0 ± 71.1) cells/field] was significantly lower than that of the native trachea [(853.5 ± 149.6) cells/ field], and the difference was statistically significant (P<0.001). Masson's trichrome staining showed that the tissue structure of genipin cross -linked decellularized trachea was more complete. Blood cell analysis and type II collagen test results showed that genipin cross-linked decellularized trachea transplanted with bone marrow mesenchymal stem cells after transplantation in situ has little rejection and can be converted into chondrocytes by the action of related growth factors in vivo. Conclusions Genipin cross-linked decellularized tracheal scaffold combined with stem cell transplantation can successfully construct a tracheal in situ replacement model. This study provides a strong support for the research of tissue engineering trachea.