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.
Highlights
RESULTSUmbilical cord blood CD34+ stem cells (UCB-CD34+) are a source of hematopoietic stem cells (HSC) used for the treatment of numerous diseases
Since HSC fate is bound to different factors, like bone marrow microenvironment, the communication between different cell types becomes an important mechanism of stemness maintenance and of differentiation [1]
We found that bone marrow mesenchymal stem cells (BM-MSC)-extracellular vesicles (EVs) influence UCB-CD34+ cell gene expression pattern, inducing cell survival, inhibiting cell differentiation and promoting their migration towards bone marrow
Summary
Umbilical cord blood CD34+ stem cells (UCB-CD34+) are a source of hematopoietic stem cells (HSC) used for the treatment of numerous diseases. Using IPA, we found that some of them (e.g., IL1b, CSF2, and CCL3) are under the control of genes targeted by miRNAs present in EVs (e.g., ZFP36/ miR-27b-3p and miR-423-5p, ABCA1/ miR-27b-3p) (Figure 6C) This analysis allowed to identify correlation pathways between up- and down-regulated genes driven by EVs miRNAs and having like a target function the chemotaxis of BM microenvironment cells. A significant decrease, at 2 hours (p-value < 0.01) and 24 hours (p-value < 0.01) after injection, was observed between the number of peripheral blood human cells in mice engrafted with UCB-CD34+ treated versus control (Figure 6H–6I) This analysis indicate that the EVs miRNAs induce, in UCB-CD34+ cells, the expression of different factors and receptors able to stimulate communication and movement of stem cells towards the niche microenvironment
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