Microvesicles Secreted by Nitric Oxide-Primed Mesenchymal Stromal Cells Boost the Engraftment Potential of Hematopoietic Stem Cells.

Patients with leukemia, lymphoma, severe aplastic anemia, etc. are frequently the targets of bone marrow transplantation, the success of which critically depends on efficient engraftment by transplanted hematopoietic cells (HSCs). Ex vivo manipulation of HSCs to improve their engraftment ability becomes necessary when the number or quality of donor HSCs is a limiting factor. Due to their hematopoiesis-supportive ability, bone marrow-derived mesenchymal stromal cells (MSCs) have been traditionally used as feeder layers for ex vivo expansion of HSCs. MSCs form a special HSC-niche in vivo, implying that signaling mechanisms operative in them would affect HSC fate. We have recently demonstrated that AKT signaling prevailing in the MSCs affect the HSC functionality. Here we show that MSCs primed with nitric oxide donor, Sodium nitroprusside (SNP), significantly boost the engraftment potential of the HSCs co-cultured with them via intercellular transfer of microvesicles (MVs) harboring mRNAs encoding HSC-supportive genes. Our data suggest that these MVs could be used as HSC-priming agents to improve transplantation efficacy. Since both, nitric oxide donors and MSCs are already in clinical use; their application in clinical settings may be relatively straight forward. This approach could also be applied in regenerative medicine protocols. Stem Cells 2019;37:128-138.