Fetal hematopoietic stem cell transplantation into beta-thalassemic mice

The transplantation of fetal-derived hematopoietic stem cells (HSCs) may potentially be used to treat hemoglobinopathies, immunodeficiencies, and storage diseases. The levels of donor cell engraftment needed to reconstitute the recipient's hematopoietic system are disease-dependent and remain unknown for most deficiencies. We have explored the application of fetal hematopoietic stem cell transplants for the amelioration of hemolytic disease in a murine model of beta-thalassemia. Nonirradiated neonatal homozygous beta-thalassemic mice were transplanted intraperitoneally (IP) with 10(6) fetal liver cells from syngeneic nonthalassemic murine fetal donors (14 to 16 days gestation). Donor hemoglobin was demonstrated in the peripheral blood of 9 of 14 transplant recipients at levels ranging from 8.8% to 27.1% at 30 days. The levels of engraftment in 6 of these 9 transplant chimeras remained stable or increased up to 150 days after transplantation, with levels ranging from 13.6% to 54.6% at 280 days. Three chimeras have demonstrated gradually decreasing engraftment after 200 days. The degree of engraftment correlated with clinically relevant improvement: decreased reticulocyte counts (8.4% to 15.7% in chimeras [n = 9] v 17.1% to 19.1% in controls [n = 8], P = .01), increased mean RBC deformability, and the significant reduction in extramedullary hematopoiesis and iron deposits seen on histological examination of chimeric liver and spleen. These data demonstrate that fetal HSC transplants results in significant long-term chimerism with favorable alterations in red cell characteristics, and decreased hemolytic anemia in beta-thalassemia.