Mesenchymal stromal cells enhance hematopoietic engraftment in a mouse model of autologous transplantation with high risk of engraftment failure

      Human mesenchymal stromal cells (MSC) co-transplanted with hematopoietic stem cells (HSC) reduce the risk of graft failure in patients subjected to haploidentical or unrelated donor HSC allogeneic transplants. However, there are not clear data regarding whether the engraftment facilitating role of MSCs is also maintained in an autologous transplantation setting. This is of particular importance for many HSC gene therapy clinical trials in which few numbers of HSC are available. Using a congenic HSC mouse transplantation model (Ly5.1/Ly5.2) in sublethally irradiated recipients (5 Gy), we have observed that the co-infusion of low numbers of congenic HSCs (1,500 LSK cells/mouse) with 106 adipose tissue-derived MSC/recipient (mAd-MSCs) significantly improved engraftment of transplanted recipients with donor cells. With the aim of approaching to a more clinically relevant model, we have conducted similar experiments using Fanconi anemia A (Fanca-/-) recipients. While transplants of >1,500 WT LSK donor cells resulted in donor engraftments (considered as ≥ 10% of donor cells in PB) in all WT recipients, these numbers resulted in a graft failure in 25-35% of FA recipients that received the same conditioning regimen of 5 Gy. To guarantee the engraftment of all FA recipients the infusion of at least 5,000 LSK cells per FA recipient was required, reinforcing the idea of a defective supportive hematopoietic stroma as a result of the FA mutation. Significantly, when 6.105 mAd-MSCs were co-infused with 1,500 WT LSK cells in FA recipients, all the transplanted animals showed significant hematopoietic engraftments, reaching 50% and 100% of donor cells in PB at 4 and 8 weeks after HSC transplant, respectively. Taken together, our results demonstrate the hematopoietic facilitating engraftment potential of Ad-MSCs, not only in an allogeneic context, but also in a clinically relevant model of autologous transplantation.
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