Biology subjects

Fortunato, O.

Publications and source records attributed to Fortunato, O..

2 recordsLinked to original sources

bioRxiv2022

Human platelet lysate derived extracellular vesicles enhance angiogenesis through miR-126

Objectivesextracellular vesicles (EVs) are key biological mediators of several physiological functions within the cell microenvironment. Platelets are the most abundant source of EVs in the blood. Similarly, platelet lysate (PL), the best platelet derivative and angiogenic performer for regenerative purposes, is enriched of EVs, but their role is still too poorly discovered to be suitably exploited. Here we explored the contribution of the EVs in PL, by investigating the angiogenic features extrapolated from that possessed by PL. Methodswe tested angiogenic ability and molecular cargo in 3D bioprinted models and by RNA sequencing analysis of PL-derived EVs. Resultsa subset of small vesicles is highly represented in PL. The EVs do not retain aggregation ability, preserving a low redox state in HUVEC and increasing the angiogenic tubularly-like structures in 3D endothelial bioprinted constructs. EVs resembled the miRNome profile of PL, mainly enriched of small RNAs and a high amount of miR-126, the most abundant angiogenic miRNA in platelets. The transfer of miR-126 by EVs in HUVEC after the in vitro inhibition of the endogenous form, restored angiogenesis, without involving VEGF as downstream target in this system. ConclusionsPL is a biological source of available EVs with angiogenic effects involving a miRNAs-based cargo. These properties can be exploited for targeted molecular/biological manipulation of PL, by potentially developing a product exclusively manufactured of EVs.

cell biology↗

bioRxiv2020

SDF-1/CXCR4 inhibition prevents paradoxical generation of cisplatin-induced pro-metastatic niches

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite its ineffectiveness in long-term control of metastasis. Here, we uncover the interconnected pathways subtending cisplatin-induced metastasis promotion. We report that cisplatin treatment of tumor-free mice results in bone-marrow expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) concomitantly with increased levels in the lungs of stromal SDF-1, the CXCR4 ligand. In experimental metastasis assays, cisplatin-induced IM favor tumor cells extravasation and expansion of CD133+CXCR4+ metastasis initiating cells (MICs), facilitating lung metastasis formation. At the primary tumor, cisplatin reduces tumor size but induces tumor release of SDF-1 triggering MICs expansion and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IM at SDF-1-enriched distant sites also promotes spontaneous metastasis. Combination treatment with a CXCR4 inhibitor prevents cisplatin-induced IM/MICs recruitment and interaction thus precluding metastasis overgrowth. Finally, we observe in NSCLC patients specimens that SDF-1 levels are higher in platinum-treated samples and correlate with worse outcome. Our findings suggest a possible novel combination therapy based on CXCR4 blockade to control metastatic disease, paradoxically promoted by cisplatin.

cancer biology↗