Mobilization of hematopoietic stem cells in a thalassemic mouse model: implications for human gene therapy of thalassemia

Granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cells may become the preferable source of hematopoietic stem cells (HSCs) for gene therapy because of the higher yield of cells compared with conventional bone marrow harvesting. A G-CSF-associated risk of splenic rupture has been re...

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Bibliographic Details
Published in:	Human gene therapy Vol. 21; no. 3; p. 299
Main Authors:	Yannaki, Evangelia, Psatha, Nikoleta, Athanasiou, Evangelia, Karponi, Garyfalia, Constantinou, Varnavas, Papadopoulou, Anastasia, Tasouli, Athanasia, Kaloyannidis, Panayotis, Batsis, Ioannis, Arsenakis, Minas, Anagnostopoulos, Achilles, Fassas, Athanasios
Format:	Journal Article
Language:	English
Published:	United States 01-03-2010
Subjects:	Animals Disease Models, Animal Flow Cytometry Genetic Therapy Granulocyte Colony-Stimulating Factor - pharmacology Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells - metabolism Hemoglobins - physiology Humans Immunoenzyme Techniques Liver - metabolism Liver - pathology Mice Mice, Inbred C57BL Mice, Knockout Recombinant Proteins Spleen - metabolism Spleen - pathology Splenectomy Thalassemia - genetics Thalassemia - metabolism Thalassemia - therapy
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Summary:	Granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cells may become the preferable source of hematopoietic stem cells (HSCs) for gene therapy because of the higher yield of cells compared with conventional bone marrow harvesting. A G-CSF-associated risk of splenic rupture has been recognized in normal donors of HSCs, but limited information is available about the G-CSF effect in the presence of splenomegaly and extramedullary hematopoiesis. We investigated the G-CSF effect in a thalassemic mouse model (HBB(th-3)) as compared with a normal strain (C57BL/6), in terms of safety, mobilization efficacy, and distribution of stem cells among hematopoietic compartments. There was no death or clinical sequelae of splenic rupture in G-CSF-treated animals of either strain; however, hemorrhagic infarcts in the spleen were detected with low frequency in G-CSF-treated HBB(th-3) mice (12.5%). HBB(th-3) mice mobilized less effectively than C57BL/6 mice (Lin(-)Sca-1(+)c-Kit(+) cells/microl of peripheral blood mononuclear cells [PBMCs]: 90 +/- 55 vs. 255 +/- 174, respectively, p = 0.01; CFU-GM/ml PBMCs: 390 +/- 262 vs. 1131 +/- 875, p = 0.01) because of increased splenic trapping of hematopoietic stem and progenitor cells (Lin(-)Sca-1(+)c-Kit(+) cells per spleen (x10(5)): 487 +/- 35 vs. 109 +/- 19.6, p = 0.01; CFU-GM per spleen (x10(2)): 1470 +/- 347 vs. 530 +/- 425, p = 0.0006). Splenectomy restored the mobilization proficiency of thalassemic mice at comparable levels to normal mice and resulted in the development of a hematopoietic compensatory mechanism in the thalassemic liver that protected splenectomized mice from severe anemia. Our data imply that, in view of human gene therapy for thalassemia, either multiple cycles or alternative ways of mobilization may be required for a sufficient yield of transplantable HSCs. In addition, strategies to minimize the risk of G-CSF-induced splenic infarcts should be explored in a clinical setting.
ISSN:	1557-7422
DOI:	10.1089/hum.2009.077