Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to plerixafor alone.
نویسندگان
چکیده
For decades, bone marrow (BM) has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for transplants following myeloablative conditioning. At present, mobilized peripheral blood stem cells are commonly used for transplantation, particularly in the autologous setting. 1 Hematopoietic stem cells (HSCs) are maintained in their niche by binding to adhesion molecules and diverse strategies are used to promote their egress from BM to peripheral blood (PB). 2 Granulocyte-colony stimulating factor (G-CSF) represents the gold standard agent to mobilize HSPCs for transplantation. Nevertheless, other compounds have recently been tested. 3 One of the most successful mobilizing agents is plerix-afor, 4 a bicyclam molecule that selectively and reversibly antagonizes the binding of stromal cell derived factor-1 (SDF-1) on the surface of BM stromal cells, to chemokine CXC-receptor-4 (CXCR4) on HSPCs, with their subsequent mobilization in the blood. Clinical trials demonstrated that plerixafor alone safely and rapidly mobilizes HSCs in healthy donors, β-thalassemia patients and patients affected by malignancies. Characterization studies of non-human primates and human samples of plerixafor-mobilized cells in comparison to cells mobilized by G-CSF alone or in combination with plerixafor showed a different expression profile, cell composition and engrafting potential in xenotransplant models. However, these studies did not solve whether plerix-afor, G-CSF, or their combination mobilizes different primitive HSC populations. In order to define the content of HSPCs mobilized by plerixafor, CD34 + cells were isolated from leukapheresis (Plx PB), steady-state BM and BM following plerixafor administration (Plx BM) of thalassemic patients enrolled in a phase II trial of mobilization. We performed a detailed immunophenotype analysis of primitive HSPCs by using the " gold standard " cell surface markers. 12 The analysis revealed an increased frequency of long-term HSCs (LT-HSCs) and a decrease in intermediate HSCs (INT-HSCs) in Plx PB versus BM. Moreover, multi-potent progenitor (MPP) frequency was lower in Plx PB samples as compared to BM and Plx BM, indicating that they are not predominantly mobilized by plerixafor (Figure 1A,B). To identify the molecular mechanisms underlying the higher quality of plerixafor-mobilized HSPCs, gene expression profiling was performed on CD34 + cell samples isolated from the same individuals (n=3). Principal component analysis (PCA) revealed a segregation of Plx PB, BM and Plx BM in three discrete clusters on the basis of the cell source (Figure 1C). Plx BM samples were positioned between Plx PB and BM, suggesting that the tran-scriptional profile begins to change by plerixafor administration …
منابع مشابه
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ورودعنوان ژورنال:
- Haematologica
دوره 102 4 شماره
صفحات -
تاریخ انتشار 2017