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Prolonged T-cell immunodeficiency following HLA- incompatible hematopoietic stem cell transplantation (HSCT) represents a major obstacle hampering the more widespread use of this approach. Strategies to fasten T-cell reconstitution in this setting are highly warranted as opportunistic infections and an increased risk of relapse account for high rates of morbidity and mortality especially during early month following this type of HSCT. We have implemented a feeder free cell system based on the use of the notch ligand DL4 and cytokines allowing for the in vitro differentiation of human T-Lymphoid Progenitor cells (HTLPs) from various sources of CD34+ hematopoietic stem and precursor cells (HSPCs). Co- transplantion of human T-lymphoid progenitors (HTLPs) and non- manipulated HSPCs into immunodeficient mice successfully accelerated the reconstitution of a polyclonal T-cell repertoire. This review summarizes preclinical data on the use of T-cell progenitors for treatment of post- transplantation immunodeficiency and gives insights into the development of GMP based protocols for potential clinical applications including gene therapy approaches. Future clinical trials implementing this protocol will aim at the acceleration of immune reconstitution in different clinical settings such as SCID and leukemia patients undergoing allogeneic transplantation. Apart from pure cell-therapy approaches, the combination of DL-4 culture with gene transduction protocols will open new perspectives in terms of gene therapy applications for primary immunodeficiencies.

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., (© AlphaMed Press 2018.)