Aplastic anemia is a potentially life-threatening bone marrow failure in which the body stops producing enough new blood cells. Marrow transplantation, antithymocyte globulin (ATG) treatment and other approaches can vary in effectiveness in approaching marrow aplasia. Extracellular vesicles are small particles released from cells that were initially thought to present cell “junk”, and later evaluated to be involved in cell-to-cell communication and affect the phenotype of target cells. In this study, we will evaluate the capacity of mesenchymal stem cell derived-extracellular vesicles (MSC-EV) to reverse aplasia in a murine model of aplastic anemia and identify the MSC-EV associated miRNA responsible for the reversal of aplastic anemia. This AA&MDSIF research grant will give us an opportunity to address novel basic mechanisms of MSC-EV healing effects and open exciting possibilities for therapy of various marrow disorders, and by extension, potentially many other disease states.
Aplastic anemia is a blood disorder where the body doesn't make enough blood cells. Marrow transplantation, antithymocyte globulin treatment and other approaches can be variably in effectiveness in approaching marrow aplasia. Extracellular vesicles (EV) are membrane surrounded small particles released by cells. Microvesicles and exosomes are the two major types of EV, and having been found to deliver both mRNA and transcriptional modulators to target cells and affect their phenotype. We have recently demonstrated the capacity of EV from mesenchymal stem cells (MSC) reverse radiation toxicity in marrow stem cells. Therefore, in this study, we plan to investigate the capacity of MSC-derived vesicles to reverse aplasia in a murine model of aplastic anemia.
In the first year of our research, we have been able to evaluate the stimulation of hematopoiesis in normal murine marrow by in vitro and in vivo exposure of hematopoietic cells to EVs. We found that the combined exosome and microvesicle fractions were superior to the exosome and microvesicle fractions in the stimulation of murine hematopoietic cell line, FDC-P1 cells. We demonstrated that the MSC-EV exposure could partially reverse aplasia in the myleran treated mouse model of aplastic anemia. To identify the MSC-EV associated miRNA responsible for the reversal aplastic anemia, we have identified miRNAs profile of three fractions vesicles by deep sequencing and are evaluating the effect of MSC-EV associated miRNA candidates on reversal of aplastic anemia.