Significant impact of mesenchymal stromal cell co-transplantation in a challenging hematopoietic engraftment scenario comparing two administration routes

Background & Aim Previous studies have shown that the co-infusion of mesenchymal stromal cells (MSCs) with hematopoietic stem cells (HSCs) enhances HSC engraftment in animal models and even in human transplants with a high risk of graft failure. These studies suggest that MSCs interact with HSCs and transport them towards the bone marrow. Although in conventional hematopoietic transplants HSCs are infused by the intravenous route (IV), some studies propose the intrabone route (IB) as an effective alternative procedure to improve HSCs homing. However, few studies have been published comparing the effectiveness of both alternatives in co-transplantation of HSCs with MSCs and the results are inconclusive. For that reason, the aim of this study was to go into detail about the comparison of both administration routes in order to enhance the hematopoietic engraftment. Methods, Results & Conclusion We investigated the possible beneficial effect of 500,000 human adipose tissue-derived MSCs improving the engraftment of a very limited number of human cord blood HSCs (4,000 CD34+ HSCs) in a xenogeneic transplant model in NSG mice, comparing both routes of transplant administration: IV and IB. Analyzing the percentage of human CD45+ cells in peripheral blood, bone marrow and spleen, the results revealed that co-transplantation with MSCs improved hematopoietic engraftment in NSG recipients conditioned with a submyeloablative irradiation dose, regardless of the route used for transplantation. In all instances, engrafted cells were also able to differentiate towards the lymphoid and myeloid linages. Furthermore, we showed that, in this model, the most efficient route of transplant administration is the IV route, obtaining higher levels of human hematopoietic engraftment in all the organs analyzed compared to those obtained by the IB route. Finally, we demonstrated that HSCs transplanted by IB route were not retained in the transplantation site and could migrate to the contralateral leg and also to the spleen. This observation could reveal that IB transplantation directly into the bone marrow niche is not preventing the recirculation and the systemic loss of the HSCs that occur when cells are IV transplanted. Taken together, our results demonstrate that IV co-transplantation of MSCs significantly increase the engraftment of very low numbers of HSCs, suggesting that this approach could be relevant in the clinics, particularly in gene therapy clinical trials in which a limited amount of HSCs is available.