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
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Luciana De Luca1, Stefania Trino1, Ilaria Laurenzana1, Vittorio Simeon1, Giovanni Calice1, Stefania Raimondo2, Marina Podestà3, Michele Santodirocco4, Lazzaro Di Mauro4, Francesco La Rocca1, Antonella Caivano1, Annalisa Morano1, Francesco Frassoni5, Daniela Cilloni2, Luigi Del Vecchio6,7,*, Pellegrino Musto8,*
1Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028, Italy
2Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy
3Stem Cell Center, S. Martino Hospital, Genova 16132, Italy
4Transfusion Medicine Unit, Puglia Cord Blood Bank, IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013, Italy
5Laboratorio Cellule Staminali post natali e Terapie Cellulari, Giannina Gaslini Institute, Genova 16148, Italy
6CEINGE-Biotecnologie Avanzate S.C.a R.L., Naples, 80145, Italy
7Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples 80131, Italy
8Scientific Direction, IRCCS-Centro di Riferimento Oncologico Basilicata (CROB), Rionero in Vulture, 85028, Italy
*These authors contributed equally to this work
Luciana De Luca, e-mail: [email protected]
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
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.
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