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首页> 外文期刊>Journal of Translational Medicine >Optimal ex vivo expansion of neutrophils from PBSC CD34+ cells by a combination of SCF, Flt3-L and G-CSF and its inhibition by further addition of TPO
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Optimal ex vivo expansion of neutrophils from PBSC CD34+ cells by a combination of SCF, Flt3-L and G-CSF and its inhibition by further addition of TPO

机译：通过SCF，FLT3-L和G-CSF的组合通过SCF，FLT3-L和G-CSF组合最佳地扩增来自PBSC CD34 +细胞的嗜中性粒细胞及其抑制作用

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Background Autologous mobilised peripheral blood stem cell (PBSC) transplantation is now a standard approach in the treatment of haematological diseases to reconstitute haematopoiesis following myeloablative chemotherapy. However, there remains a period of severe neutropenia and thrombocytopenia before haematopoietic reconstitution is achieved. Ex vivo expanded PBSC have been employed as an adjunct to unmanipulated HSC transplantation, but have tended to be produced using complex cytokine mixtures aimed at multilineage (neutrophil and megakaryocyte) progenitor expansion. These have been reported to reduce or abrogate neutropenia but have little major effect on thrombocytopenia. Selective megakaryocyte expansion has been to date ineffective in reducing thrombocytopenia. This study was implemented to evaluate neutrophil specific rather than multilineage ex vivo expansion of PBSC for specifically focusing on reduction or abrogation of neutropenia. Methods CD34+ cells (PBSC) were enriched from peripheral blood mononuclear cells following G-CSF-mobilisation and cultured with different permutations of cytokines to determine optimal cytokine combinations and doses for expansion and functional differentiation and maturation of neutrophils and their progenitors. Results were assessed by cell number, morphology, phenotype and function. Results A simple cytokine combination, SCF + Flt3-L + G-CSF, synergised to optimally expand and mature neutrophil progenitors assessed by cell number, phenotype, morphology and function (superoxide respiratory burst measured by chemiluminescence). G-CSF appears mandatory for functional maturation. Addition of other commonly employed cytokines, IL-3 and IL-6, had no demonstrable additive effect on numbers or function compared to this optimal combination. Addition of TPO, commonly included in multilineage progenitor expansion for development of megakaryocytes, reduced the maturation of neutrophil progenitors as assessed by number, morphology and function (respiratory burst activity). Conclusion Given that platelet transfusion support is available for autologous PBSC transplantation but granulocyte transfusion is generally lacking, and that multilineage expanded PBSC do not reduce thrombocytopenia, we suggest that instead of multilineage expansion selective neutrophil expansion based on this relatively simple cytokine combination might be prioritized for development for clinical use as an adjunct to unmanipulated PBSC transplantation to reduce or abrogate post-transplant neutropenia.
机译：背景技术自体动员外周血干细胞（PBSC）移植现在是治疗血液化化疗后重建血液疾病的标准方法。然而，在达到呕血重构之前，仍有一段时间的严重中性蛋白和血小板减少症。 exvivo扩展的PBSC已被用作非法HSC移植的辅助，但是使用旨在旨在的复杂细胞因子混合物来生产祖先（中性粒细胞和Megakaryocyte）祖细胞膨胀。据报道，这些是减少或废除中性粒细胞减少，但对血小板减少症几乎没有重大影响。选择性巨核细胞扩张已经迄今为止在还原血小板减少症时无效。实施该研究以评估嗜中性粒细胞特异性，而不是PBSC的多素exvivo扩展，以专门关注细胞减少症的减少或消除。方法方法CD34 + 细胞（pbsc）从G-CSF动员后的外周血单核细胞富集，并用细胞因子的不同置换培养以确定最佳的细胞因子组合和剂量，用于膨胀和功能分化和中性粒细胞成熟及其祖先。结果通过细胞数，形态，表型和功能评估。结果简单的细胞因子组合，SCF + FLT3-L + G-CSF，改变为通过细胞数，表型，形态学和功能（通过化学发光测量的超氧化物呼吸爆发）评估的最佳膨胀和成熟的中性粒细胞祖细胞。 G-CSF出现功能成熟的强制性。与这种最佳组合相比，添加其他常用的细胞因子，IL-3和IL-6对数量或功能没有明显的添加剂效果。添加TPO，通常包括在多线粒祖细胞的膨胀中，降低了通过数量，形态和功能（呼吸爆发活性）评估的中性粒细胞祖细胞的成熟。结论鉴于血小板输注载体可用于自体PBSC移植，但通常缺乏粒细胞输血，并且多线粒扩增的PBSC不会减少血小板减少症，而不是基于这种相对简单的细胞因子组合的多线性扩增选择性中性粒细胞扩增可能优先考虑临床用作临床用作未占用的PBSC移植的辅助，以减少或废除移植后的中性粒细胞凋亡。

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