MicroRNA-191 regulates differentiation and migration of mesenchymal stem cells and their paracrine effect on angiogenesis.

MicroRNAs (miRNAs) are critical regulators in organ development. Among them, miR-191 is known to be regulated in early embryogenesis and dysregulated in cancer. This role in undifferentiated tissues suggests a possible part of miR-191 also in bone marrow derived mesenchymal stem cells (BMSCs) physiology. Here, we report that miR-191 decreased MMP expression and migration of BMSCs. Conditioned media of miR-191 overexpressing BMSCs block VEGF expression, and inhibit angiogenesis of HUVECs. Under osteogenic culture conditions, inhibition of miR-191 significantly induces bone formation. Moreover, our studies showed miR-191 might influence chondrogenesis of BMSCs by directly targeting CCAAT Enhancer Binding Protein Beta (CEBPB). Taken together, here we demonstrate the role of miR-191 in differentiation, migration and paracrine function of BMSCs.

Coculture of mesenchymal stem cells and endothelial cells enhances host tissue integration and epidermis maturation through AKT activation in gelatin methacryloyl hydrogel-based skin model.

A major challenge for clinical use of skin substitutes is insufficient host tissue integration leading to loosening and partial necrosis of the implant. In this present study, a three-dimensional (3D) coculture system constructed using human umbilical cord mesenchymal stem cells (uc-MSCs) and umbilical vein endothelial cells (HUVECs) encapsulated in gelatin methacryloyl (GelMA) hydrogels was evaluated to determine the outcomes of cell-cell interactions in vitro and in vivo. The results revealed that GelMA hydrogels displayed minor cytotoxicity on both cell types. An uc-MSC:HUVEC ratio of 50:50 demonstrated the highest cell proliferation and expression of angiogenic markers. The supplement of basic fibroblast growth factors (bFGF) in coculture system further induced cell proliferation and gene expression in vitro. In vivo transplantation of this cocultured constructs efficiently enhanced the implant and host tissue integration. Additionally, the proliferation of keratinocytes was well maintained on GelMA hydrogels and the gene expression related to cell proliferation and differentiation was significantly increased in coculture system comparing to monoculture. Mechanistically, AKT signaling pathways were activated in cocultures. Our findings suggest that coculturing MSC and EC in GelMA hydrogels could be a promising approach to substantially improve the integration of exogenous skin substitutes and host tissues. STATEMENT OF SIGNIFICANCE: In this study, the co-culture of uc-MSCs and HUVECs in photocrosslinkable GelMA hydrogels significantly enhanced host tissue integration. Cell proliferation, ECM deposition and angiogenic genes expression were all substantially improved in vitro and the excellent host tissue integration into the implanted tissue was observed in vivo. When served as a dermal layer, the scaffold with co-cultured cells enhanced the proliferation and differentiation of keratinocytes. AKT signaling was proved to be involved in the regulation of cell survival and fate determination. This work demonstrated the importance of 3D cell co-culture to facilitate host tissue integration that can be a promising approach for long-term survival of skin substitutes.

Tumor Suppressor PTPRJ Is a Target of miR-155 in Colorectal Cancer.

PTPRJ is known for its antiproliferative role. Loss of heterozygosity (LOH) of PTPRJ has frequently been observed in various human cancers including colorectal cancer (CRC), lung cancer, and breast cancer. However, the function and mechanism of PTPRJ in CRC are not well understood. At the present study, we show that ectopic expression of PTPRJ inhibits cell growth, migration, and invasiveness in CRC cell line HCT116. Moreover, PTPRJ inhibits the tumorigenecity of HCT116 in a xenograft tumor model. MiR-155, the well-known oncomiR in CRC, is identified as an upstream factor of PTPRJ. MiR-155 directly binds to the 3' untranslated region of PTPRJ mRNA and suppresses the mRNA and protein levels of PTPRJ. Furthermore, the growth-promoting and AKT signaling activation effect of miR-155 was abrogated by PTPRJ overexpression, and vice versa. Our study reveals the crucial role of miR-155/PTPRJ/AKT axis in proliferation and migration of CRC cells and suggests a therapeutic potential of PTPRJ. J. Cell. Biochem. 118: 3391-3400, 2017. © 2017 Wiley Periodicals, Inc.