Mixed chimerism following in utero hematopoietic stem cell transplantation in murine models of hemoglobinopathy.

OBJECTIVE: Mixed hematopoietic chimerism after bone marrow transplantation can provide effective treatment for beta-thalassemia because of the selective advantage that exists for donor erythropoiesis. In utero hematopoietic stem cell transplantation (IUHSCTx) can achieve mixed hematopoietic chimerism, particularly when a selective advantage exists for donor cells. To investigate the biology of IUHSCTx in hemoglobinopathies, we performed fully allogeneic IUHSCTx in murine models of beta-thalassemia (Thal) and sickle cell disease (SCD).
MATERIALS AND METHODS: We serially assessed and compared levels of mononuclear cell (MNC) and erythroid chimerism after IUHSCTx of either adult bone marrow (BM)- or fetal liver (FL)-derived allogeneic donor cells in the two hemoglobinopathy models, which differ significantly in their degree of anemia (Thal>>SCD) and red cell half-life (Thal<<SCD).
RESULTS: The mean level of donor MNC chimerism was higher for SCD and Thal chimeras receiving FL- compared to adult BM-derived donor cells and tended to increase over time in the FL recipients. Donor hemoglobin (Hb) levels also were higher in all groups receiving FL compared to adult BM. Donor Hb levels in chimeric Thal mice were significantly higher than those in SCD or wild-type mice. Hematologic parameters such as Hb, hematocrit (Hct), mean cell volume (MCV), membrane-associated denatured Hb, and the oxygen equilibration curve were improved in chimeric hemoglobinopathy mice. However, the improvement in Hb, Hct, and MCV was not sustained despite stable levels of donor leukocyte engraftment.
CONCLUSION: The severity of the hemoglobinopathy being treated and the source of donor cells may be important determinants of success in the treatment of hemoglobinopathy by IUHSCTx.