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Delineation of Cell Cycle State and Correlation to Adhesion Molecule Expression of Human CD34⁺ Cells from Steady-State Bone Marrow and Peripheral Blood Mobilized Following G-CSF-Supported Chemotherapy

^a Department of Internal Medicine V, University of Heidelberg;
^b German Cancer Research Center, Division D 0200, Heidelberg;
^c III. Medizinische Klinik, Klinikum Mannheim, University of Heidelberg, Heidelberg, Germany

Key Words. Adhesion antigens • CD34 • CD49d • Cell cycle • Cyclins • Hematopoietic stem cells • Human • Ki-67

Dr. Stefan Fruehauf, Department of Internal Medicine V, University of Heidelberg, Hospitalstrasse 3, D-69115 Heidelberg, Germany.

Treatment with a combination of chemotherapy and G-CSF leads to the release of hematopoietic stem cells from the bone marrow (BM) to the peripheral blood (PB), where they can be harvested for transplantation. Premobilization BM CD34⁺ cells were reported to proliferate actively, while virtually none of the mobilized PB CD34⁺ cells were in the S/G₂M phase. We were interested in elucidating the cell cycle state further and in investigating the role of adhesion molecule expression on marrow-adherent and circulating CD34⁺ cells during different phases of the cell cycle. Consecutive premobilization BM and leukapheresis product (LP) samples were obtained from 14 patients following G-CSF-supported chemotherapy. Steady-state BM and LP CD34⁺ selected cells were triple-stained for CD34, for DNA using the intercalating dye 7-aminoactinomycin D, and for Ki-67, cyclins, or adhesion antigens. Ki-67 is expressed in all phases of the cell cycle except G₀ and was found in 69.14% ± 3.46% (mean ± standard error [SE]) of BM CD34⁺ cells and 62.78% ± 3.37% of LP CD34⁺ cells, while in BM significantly more CD34⁺/Ki-67⁺ cells were in the S/G₂M phase of the cell cycle than in LP (8.6% ± 0.9% versus 1.8% ± 0.3%, respectively, p = 0.0001). Therefore, most circulating mobilized CD34⁺ cells are in the G₁ phase, similar to their steady-state BM counterparts. Cyclin A became detectable in the 2n DNA peak. As expected, a higher proportion of CD34⁺/cyclin A⁺/S/G₂M cells was found in BM than in LP (p < 0.05). Antigen density of the cyclins D₃ and D₂ tended to be higher on LP than on BM CD34⁺ cells, while D₁ was found at low levels in similar density. The adhesion antigens CD18, CD49b, CD49d, CD49e, CD58, and CD62L were expressed in a significantly higher proportion of S/G₂M-phase than in G₀/G₁-phase CD34⁺ cells. The strongest association to the proliferative status was observed for CD49d, which was coexpressed by 85.9% ± 2.6% (BM) or 90.8% ± 2.5% (LP) of CD34⁺/S/G₂M cells, whereas a distinct CD34⁺/CD49d^–/S/G₂M population could not be detected. The average coexpression of the other antigens was 57% (CD49e, CD18) or lower. Our results demonstrate that the majority of PB CD34⁺ cells mobilized following G-CSF-supported chemotherapy and steady-state BM CD34⁺ cells are in the late G₁ phase of the cell cycle and show a correlation between the expression of adhesion receptors and cell cycle status of CD34⁺ cells in both BM and LP.

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