MiRNAs and piRNAs from bone marrow mesenchymal stem cell extracellular vesicles induce cell survival and inhibit cell differentiation of cord blood hematopoietic stem cells: a new insight in transplantation

Abstract

// Luciana De Luca 1 , Stefania Trino 1 , Ilaria Laurenzana 1 , Vittorio Simeon 1 , Giovanni Calice 1 , Stefania Raimondo 2 , Marina Podestà 3 , Michele Santodirocco 4 , Lazzaro Di Mauro 4 , Francesco La Rocca 1 , Antonella Caivano 1 , Annalisa Morano 1 , Francesco Frassoni 5 , Daniela Cilloni 2 , Luigi Del Vecchio 6, 7, * , Pellegrino Musto 8, * 1 Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028, Italy 2 Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy 3 Stem Cell Center, S. Martino Hospital, Genova 16132, Italy 4 Transfusion Medicine Unit, Puglia Cord Blood Bank, IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013, Italy 5 Laboratorio Cellule Staminali post natali e Terapie Cellulari, Giannina Gaslini Institute, Genova 16148, Italy 6 CEINGE-Biotecnologie Avanzate S.C.a R.L., Naples, 80145, Italy 7 Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples 80131, Italy 8 Scientific Direction, IRCCS-Centro di Riferimento Oncologico Basilicata (CROB), Rionero in Vulture, 85028, Italy * These authors contributed equally to this work Correspondence to: Luciana De Luca, e-mail: dr.luciana.deluca@gmail.com Keywords: mesenchymal stem cells, extracellular vesicles, umbilical cord blood stem cells, microRNAs, piRNAs Received: June 15, 2015      Accepted: December 05, 2015      Published: December 29, 2015 ABSTRACT Hematopoietic stem cells (HSC), including umbilical cord blood CD34+ stem cells (UCB-CD34+), are used for the treatment of several diseases. Although different studies suggest that bone marrow mesenchymal stem cells (BM-MSC) support hematopoiesis, the exact mechanism remains unclear. Recently, extracellular vesicles (EVs) have been described as a novel avenue of cell communication, which may mediate BM-MSC effect on HSC. In this work, we studied the interaction between UCB-CD34+ cells and BM-MSC derived EVs. First, by sequencing EV derived miRNAs and piRNAs we found that EVs contain RNAs able to influence UCB-CD34+ cell fate. Accordingly, a gene expression profile of UCB-CD34+ cells treated with EVs, identified about 100 down-regulated genes among those targeted by EV-derived miRNAs and piRNAs (e.g. miR-27b/MPL, miR-21/ANXA1, miR-181/EGR2 ), indicating that EV content was able to modify gene expression profile of receiving cells. Moreover, we demonstrated that UCB-CD34+ cells, exposed to EVs, significantly changed different biological functions, becoming more viable and less differentiated. UCB-CD34+ gene expression profile also identified 103 up-regulated genes, most of them codifying for chemokines, cytokines and their receptors, involved in chemotaxis of different BM cells, an essential function of hematopoietic reconstitution. Finally, the exposure of UCB-CD34+ cells to EVs caused an increased expression CXCR4, paralleled by an in vivo augmented migration from peripheral blood to BM niche in NSG mice. This study demonstrates the existence of a powerful cross talk between BM-MSC and UCB-CD34+ cells, mediated by EVs, providing new insight in the biology of cord blood transplantation.