Abstract
Characterization of hematopoiesis/erythropoiesis in thalassemias from multipotent primitive cells to mature erythrocytes is of fundamental importance and clinical relevance. We investigated this process in alpha- and beta-globin hemizygous mice, lacking the two adult tandemly organized genes from either the alpha- or beta-globin locus. Although both mice backcrossed on a homogeneous background exhibited similar reduced red blood cell (RBC) survival, beta-globin hemizygous mice had less severe reticulocyte loss and globin chain imbalance, suggesting an apparently milder thalassemia than for alpha-globin hemizygous mice. In contrast, however, beta-globin hemizygous mice displayed a more marked perturbation of hematologic parameters. Quantification of erythroid precursor subpopulations in marrow and spleen of beta-globin hemizygous mice showed more severely impaired maturation from the basophilic to orthochromatophilic erythroblasts and substantial loss of these late precursors probably as a consequence of a greater susceptibility to an excess of free alpha-chain than beta-chain. Hence, only erythroid precursors exhibiting stochastically moderate chain imbalance would escape death and mature to reticulocyte/RBC stage, leading to survival and minimal loss of reticulocytes in the beta-globin hemizygous mice. Furthermore, in response to the ineffective erythropoiesis in beta-globin hemizygous mice, a dynamic compensatory hematopoiesis was observed at earlier differentiation stage as evidenced by a significant increase of erythroid progenitors (erythroid colony-forming units approximately 100-fold) as well as of multipotent primitive cells (day 12 spleen colony-forming units approximately 7-fold). This early compensatory mechanism was less pronounced in alpha-globin hemizygous mice. The expansion of multipotent primitive and potentially stem cell populations, taken together with ineffective erythropoiesis and increased reticulocyte/RBC destruction could confer major cumulative advantage for gene targeting/bone marrow transplantation. Therefore, this study not only corroborated the strong potential effectiveness of transplantation for thalassemic hematopoietic therapy but also demonstrated the existence of a differential regulatory response for alpha- and beta-thalassemia.
Highlights
Thalassemia, among the most frequent of inherited diseases, constitutes a heterogeneous disorder based on clinical severity, pathophysiology, and molecular changes
We investigated whether soluble globin chain levels were imbalanced at three short time periods of de novo synthesis in reticulocytes and at steady state in peripheral blood, which consisted of more than 99.4% reticulocytes and red blood cell (RBC)
To assess whether the differential response between the hemi-thal and hemi-␣thal mice is due to an increased tendency of the excess ␣-globin chains from hemithal to associate with erythroid cell membranes, we have monitored the levels of globin chains in reticulocyte membranes in these mice as a function of total protein (Table II)
Summary
Thalassemia, among the most frequent of inherited diseases, constitutes a heterogeneous disorder based on clinical severity, pathophysiology, and molecular changes. The morbidity and mortality associated with this procedure as well as the difficulty in obtaining histocompatible donors remain problematic [11, 12] These problems could potentially be alleviated by the use of autologous bone marrow transplantation following gene therapy correction. In both cases, a detailed characterization of the altered hematopoiesis and erythropoiesis in ␣- and -thalassemia is necessary to develop an effective cure for thalassemic patients. A thorough characterization of hematopoiesis/erythropoiesis in these globin hemizygous mice is required to determine the fundamental cellular defects and whether these mice reproduce the human diseases, as these globin hemizygous mice are becoming widely used as models of human thalassemia. We report such an investigation in these ␣- and -globin hemizygous mice both bred and compared for the first
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
