Cotransplantation of Umbilical Cord Mesenchymal Stem Cells Promotes the Engraftment of Umbilical Cord Blood Stem Cells in Iron Overload NOD/SCID Mice

Iron overload aggravates the difficulty of umbilical cord blood (UCB) stem cell engraftment and reduces the survival of patients undergoing hematopoietic stem cell (HSC) transplantation. Mesenchymal stem cells (MSCs) have been suggested to have a significant role in HSC engraftment. This study aimed to determine the effect of intra-bone marrow (IBM) and i.v. cotransplantation of UBC mononuclear cells (MNCs) and umbilical cord (UC) MSCs on engraftment and hematopoietic recovery in an iron overload hematopoietic microenvironment. The iron overload model was established by dose-escalation intraperitoneal injection of iron dextran in NOD/SCID mice. Iron deposition in the bone marrow, heart, and liver was examined using hematoxylin and eosin (H&E) staining. Serum levels of ferritin and iron status in the liver were measured. The iron overload NOD/SCID mice were sublethally irradiated and divided into 5 groups for transplantation: (1) control group; (2) IBM+ group: IBM injection of combined UCB-MNCs/UC-MSCs; (3) IV+ group: i.v. injection of combined UCB-MNCs/UC-MSCs; (4) IBM group: IBM injection of only UCB-MNCs; and (5) IV group: i.v. injection of UCB-MNCs. At 6 weeks after transplantation, the human CD45+ cells in the bone marrow were analyzed by flow cytometry. The semiquantitative analysis of vascular endothelial growth factor (VEGF-A), osteopontin (OPN), and stromal cell-derived factor-1a (SDF-1a) were examined by immunohistochemical staining (IHC). Compared with the IBM and IV groups, the survival rate and the percentages of human CD45+ cells and CD34+ cells and colony-forming units (CFU) in bone marrow were elevated in the IBM+ and IV+ groups. In addition, the levels of VEGF-A, OPN, and SDF-1a in bone marrow were all higher in the IBM+ and IV+ groups. Our data show that IBM and i.v. cotransplantation of UC-MSCs can improve the engraftment and proliferation of UCB-MNCs in iron overload NOD/SCID mice. The increased expression of VEGF-A, OPN, and SDF-1a in the bone marrow may be involved in improving the hematopoietic microenvironment and promoting the implantation of human UCB stem cells in the bone marrow with iron overload.