Adipose tissue-derived stem cells boost vascularization in grafted ovarian tissue by growth factor secretion and differentiation into endothelial cell lineages.

Adipose tissue-derived stem cells (ASCs) have multilineage differentiation potential, proangiogenic properties, and the ability to enhance vascularization in xenografted human ovarian tissue. The aim of the present study was to identify the mechanisms behind the proangiogenic effects of ASCs. For this purpose, severe combined immunodeficient (SCID) mice were grafted with frozen-thawed human ovarian tissue. ASCs were labeled by lentiviral transfection for expression of enhanced green fluorescent protein (eGFP), and human ovarian tissue was grafted using a previously described two-step procedure. In the control group, ovarian tissue was transplanted using the standard one-step approach. Samples were collected and analyzed after 7 days. Detection of the eGFP antigen by immunofluorescence showed ASCs surrounding and infiltrating ovarian tissue grafts. Significantly higher vessel density was observed in the ASC group (P = 0.0182 versus control) on Day 7. Co-expression of eGFP, CD34 and CD31 was demonstrated in human vessels, confirming ASC differentiation into human endothelial cell lineages. Increased gene expression of vascular endothelial growth factor (VEGF) was also shown in the ASC group (P = 0.0182 versus control). Immunohistochemistry targeting anti-human VEGF revealed significantly higher expression levels in the ASC group (P = 0.033 versus control), while VEGF and eGFP immunofluorescence showed greater growth factor expression in areas surrounding ASCs. In conclusion, ASCs differentiate into human vessels and promote secretion of VEGF when transplanted together with human ovarian tissue to SCID mouse peritoneum using a two-step ovarian tissue grafting procedure. This is a promising step towards potentially improving ovarian tissue quality and lifespan. Long-term studies should be conducted to investigate ASC safety and efficacy in the context of ovarian tissue transplantation.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration.

The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins. In this study, we found that glucose deprivation dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this posttranslational induction could be recapitulated using glycolysis inhibition, hypoxia, oxidative phosphorylation (OXPHOS) inhibitor rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes accumulated, including in cell protrusions of the plasma membrane. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration increased in cells overexpressing MCT1 and CD147, but it was inhibited in glucose-starved cells provided with an alternative oxidative fuel, treated with an antioxidant, lacking MCT1 expression, or submitted to pharmacological MCT1 inhibition. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer.