Upregulation of fetal hemoglobin in adult-derived erythroid progenitors
Abstract
In patients with adult hemoglobin disorders including sickle cell disease and β thalassemia, increased levels of fetal hemoglobin (Hb F) reduces disease severity, morbidity and mortality. It is therefore, important to identify agents that increase Hb F and to understand the mechanism by which these agents act to change the hemoglobin profile. Using hematopoietic progenitor cells (HPCs) isolated from human peripheral blood, we established a completely defined, serum-free in vitro culture system in which cells proliferate, mature and express the developmentally-correct balance of adult and fetal hemoglobin. We added sodium butyrate (NaBut), thyroid hormone (T3), and dimethyloxallyl glycine (DMOG) singly or in combination to developing HPCs, and assessed for dose-dependent effects on proliferation, viability, erythroid differentiation and changes in globin mRNA and hemoglobin profile. We found that early exposure of cells to NaBut resulted in maximal upregulation of γ-globin mRNA levels and Hb F at 0.4 mM, while higher concentrations yielded significant cell death. Treatment of cells with T3 led to an increase in erythroid cell maturation and Hb F levels. DMOG also increased Hb F levels, and in cultures from two of three donors, Hb F levels further increased when T3 was also present. The data support a mechanism in which these agents affect the proliferative capacity of HPCs and increase the fetal globin transcriptional potential. Our findings, especially the effects of T3 and DMOG on Hb F levels set the stage for further studies of such agents and support the potential use of combination therapy to achieve optimal Hb F induction in patients with sickle cell disease and β thalassemia.
Subject Area
Molecular biology|Genetics|Cellular biology
Recommended Citation
Banini, Bubu Ama, "Upregulation of fetal hemoglobin in adult-derived erythroid progenitors" (2009). ProQuest ETD Collection - Thomas Jefferson University. AAI3415771.
https://jdc.jefferson.edu/dissertations/AAI3415771
