Differential regulatory and compensatory responses in hematopoiesis/erythropoiesis in alpha- and beta-globin hemizygous mice.
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.
Institut de Recherches Cliniques de Montréal, Molecular Genetics and Development, Faculte de Medecine de L'Universite de Montréal, 110 Pine Avenue West, Montréal, Québec H2W 1R7, Canada.
Hugues
H
Beauchemin
Marie-José
MJ
Blouin
Marie
M
Trudel
D000818:Animals; D019921:Biotinylation; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002469:Cell Separation; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D003433:Crosses, Genetic; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology; D004920:Erythropoiesis / Q000502:physiology*; D005434:Flow Cytometry; D005914:Globins / Q000235:genetics* / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology*; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D012156:Reticulocytes / Q000166:cytology; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D017085:alpha-Thalassemia / Q000473:pathology; D017086:beta-Thalassemia / Q000473:pathology
D005914:Globins