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

Stem cell transplantation is the only curative therapy for several malignant and non-malignant diseases. However, its efficacy critically depends on the quality and quantity of the hematopoietic stem cells (HSCs) present in the graft. This article reports a novel finding that mesenchymal stromal cells primed with nitric oxide secrete microvesicles that are enriched in mRNAs encoding HSC-supportive genes. Results of this study show that HSCs briefly contacted with these primed vesicles possess significantly improved engraftment ability. Application of these vesicles as HSC-priming agents would significantly improve the efficacy of clinical transplants. These data could have implications in other stem cell-based therapies as well.