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Shipounova et al. abstract (clones)

Please cite this article as follows: Shipounova (Nifontova) I, Sats N, Svinareva D, Petrova T, Drize N, Savchenko V. Clonal composition of hematopoietic tissue in reconstituted mice after repeated treatment with G-CSF. Cell Ther Transplant. 2008;1:e.000017.01. doi:10.3205/ctt-2008-en-000017.01


Clonal composition of hematopoietic tissue in reconstituted mice after repeated treatment with G-CSF

Irina Shipounova (Nifontova), Natalia Sats, Daria Svinareva, Tatiana Petrova, Nina Drize, Valeriy Savchenko
Abstract

Introduction: Previous studies have shown that hematopoiesis in mice reconstituted with retrovirally-marked HSC is caused by multiple, mainly short-lived clones. Such clonal kinetics suggests the exhaustion of hematopoietic clones followed by the subsequent recruiting of new clones via proliferation (clonal succession).
Materials and methods: In this study, clonal hematopoiesis was studied in a murine model, whereas reconstitution of hematopoiesis was studied with bone marrow (BM) cells expressing the human adenosine deaminase (hADA) gene, or in sex-mismatched donor/recipient pairs. Following irradiation at a lethal dose, the test mice were transplanted with BM from 5-FU-treated donor mice. CFU assays in female irradiated mice were performed using a spleen cell colony assay, according to Till-McCulloch. The CFU origin of reconstituted mice was traced by means of sex-linked smc gene of donors, or by a hADA gene marker introduced into the donor cells by short-term retroviral transfection. GM-CSF treatment of the reconstituted mice was performed monthly for up to 6 months.
Results: Repeated G-CSF treatment did not affect the numbers of leukocytes and proportion of granulocytes in the peripheral blood of the reconstituted mice. The concentration of CFU-S in the bone marrow of the reconstituted mice did not change after G-CSF treatment. 100% donor chimerism is rare among reconstituted mice; a partial reversal to the hematopoiesis recipient marrow is usually observed. The monthly proportion of donor CFU-S varied from 35 to 88%. In reconstituted mice that were not treated with G-CSF, the proportion of donor CFU-S was significantly higher than in the groups that were treated (71.2±6.9% versus 56.5±5.3%, р<0.05).
The proportion of ADA gene-transduced CFU-S in the G-CSF treated group was lower and more stable than the non-treated cases (20.6±7.1% versus 45.7±6.3%). Analysis of individual clones in both untreated and treated animals did not reveal significant differences in their average number. However, the size of the clones decreased significantly upon treatment, as clones were represented by fewer colonies. Long-lived clones (detected at >3 months) were not observed after G-CSF treatment.
Conclusion: Repeated injections of G-CSF in pharmacological amounts cause an imbalance of the hematopoietic system. The long-term consequences of HSCs mobilization using G-CSF need to be carefully monitored in potential donors.

Keywords: hematopoietic stem cells, colony forming unit-spleen (CFU-S), retroviral gene transfer, G-CSF

Please cite this article as follows: Shipounova (Nifontova) I, Sats N, Svinareva D, Petrova T, Drize N, Savchenko V. Clonal composition of hematopoietic tissue in reconstituted mice after repeated treatment with G-CSF. Cell Ther Transplant. 2008;1:e.000017.01. doi:10.3205/ctt-2008-en-000017.01


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