Single cell dissociation antibody staining and FACS sorting Cellular atlas DEGs Cellular interaction Ligand Recepto r Immunostaining Functional assays Correlation analysis Droplet-based scRNA-seq Data Cell 1 Cell 2 Cell x Gene 1 Gene 2 Gene y Highlights Single cell transcriptomic datasets are a valuable resource to dissect cellular diversity and intercellular crosstalk of human ICCs. Malignant cells displayed remarkable inter-tumor heterogeneity and Tregs revealed highly immunosuppressive characteristics. Six distinct fibroblast subsets were defined in ICCs and adjacent tissues. CD146 + vCAFs, comprising most of the fibroblasts, had tight interactions with malignant cells through IL-6/IL-6R axis. Tumor exosomal miR-9-5p elicited IL-6 expression in vCAFs, contributing to ICC progression via upregulation of EZH2.

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Up to now, the gingiva-derived mesenchymal stem cells (GMSCs) as a new postnatal stem cells have been isolated and characterized with multipotential differentiation capabilities in vitro. However, the in vivo efficacy of utilizing the GMSCs in bone regeneration remains obscure. First of all, we identified canonical MSCs in human gingival tissue, which possessed homogenous immunophenotype (CD34(-)CD45(-)CD29(+)CD105(+)CD90(+) STRO-1(+)) and had tri-lineage differentiation potential (osteoblasts, adipocytes, and chondrocytes). Next, we examined the efficacy of utilizing these stem cells in bone tissue regeneration; the enhanced green fluorescent protein-labeled GMSCs seeded on type I collagen gel were implanted into the mandibular defects as well as the critical-sized calvarial defects in Sprague Dawley rats. We first demonstrated that GMSCs could repair the mandibular wounds and calvarial defects at 2 months in rats postsurgical reconstruction. Histomorphological analysis and image of fluorescence microscope certified that new bone in the defect areas was derived from the transplanted GMSCs. Immunohistochemical analysis of green fluorescent protein, human collagen I, and osteopontin further confirmed our conclusion. The above results implied that mesenchymal stem cells derived from gingival tissue could be a novel source for stem cell-based therapy in bone reconstruction in clinical applications.

Cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic micro-RNA (miR)-155 in HCC cells was significantly up-regulated by coculture with LCMSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the down-regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. Conclusion: S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013;57:2274-2286 T he tumor microenvironment plays an important role in modulating cancer and cancer stem cell progression. 1,2 Recently, mesenchymal stem cells (MSCs), as a pivotal part of the tumor stroma, have attracted great attention for their ability to participate in tumor proliferation 3 and metastasis. 4 Although several lines of evidence demonstrate that MSCs can be activated by cancer cells and contribute to tumor progression, the Abbreviations:: cDNA, complementary DNA; ELISA, enzyme-linked immunosorbent assay; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; LCMSCs, liver cancer-associated MSCs; LN-MSCs, liver normal MSCs; miRNA, microRNA; miR-155, microRNA-155; MMP9, matrix metalloproteinases 9; MSCs, mesenchymal stem cells; qRT-PCR, quantitative real time polymerase chain reaction; siRNA, small interfering RNA; SOCS1, suppressor of cytokine signaling 1; STAT, signal transducer and activator of transcription.From the