CEA/DSV/iRCM/LRTS, Fontenay-aux-Roses, France.
Haematologica. 2012 Apr;97(4):491-9. doi: 10.3324/haematol.2011.047662. Epub 2011 Dec 16.
Although mobilization of hematopoietic stem cells and hematopoietic progenitor cells can be achieved with a combination of granulocyte colony-stimulating factor and plerixafor (AMD3100), improving approaches for hematopoietic progenitor cell mobilization is clinically important.
Heparan sulfate proteoglycans are ubiquitous macromolecules associated with the extracellular matrix that regulates biology of hematopoietic stem cells. We studied the effects of a new family of synthetic oligosaccharides mimicking heparan sulfate on hematopoietic stem cell mobilization. These oligosaccharides were administered intravenously alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 in mice. Mobilized hematopoietic cells were counted and phenotyped at different times and the ability of mobilized hematopoietic stem cells to reconstitute long-term hematopoiesis was determined by competitive transplantation into syngenic lethally irradiated mice followed by secondary transplantation.
Mimetics of heparan sulfate induced rapid mobilization of B-lymphocytes, T-lymphocytes, hematopoietic stem cells and hematopoietic progenitor cells. They increased the mobilization of hematopoietic stem cells and hematopoietic progenitor cells more than 3-fold when added to the granulocyte colony-stimulating factor/AMD3100 association. Hematopoietic stem cells mobilized by mimetics of heparan sulfate or by the granulocyte colony-stimulating factor/AMD3100/mimetics association were as effective as hematopoietic stem cells mobilized by the granulocyte colony-stimulating factor/AMD3100 association for primary and secondary hematopoietic reconstitution of lethally irradiated mice.
This new family of mobilizing agents could alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 mobilize a high number of hematopoietic stem cells that were able to maintain long-term hematopoiesis. These results strengthen the role of heparan sulfates in the retention of hematopoietic stem cells in bone marrow and support the use of small glyco-drugs based on heparan sulfate in combination with granulocyte colony-stimulating factor and AMD3100 to improve high stem cell mobilization, particularly in a prospect of use in human therapeutics.
虽然粒细胞集落刺激因子（G-CSF）和培利珠单抗（AMD3100）的联合应用可以动员造血干细胞和造血祖细胞，但改善造血祖细胞动员的方法在临床上很重要。
硫酸乙酰肝素蛋白聚糖是一种普遍存在的与细胞外基质相关的大分子，它调节造血干细胞的生物学特性。我们研究了一类新型合成寡糖对造血干细胞动员的影响。这些寡糖单独或与 G-CSF 和/或 AMD3100 联合静脉给药，在小鼠体内进行研究。在不同时间点计数动员的造血细胞并进行表型分析，通过竞争移植到同基因致死性照射的小鼠中，然后进行二次移植，确定动员的造血干细胞重建长期造血的能力。
硫酸乙酰肝素类似物诱导 B 淋巴细胞、T 淋巴细胞、造血干细胞和造血祖细胞的快速动员。当与 G-CSF/AMD3100 联合应用时，它们使造血干细胞和造血祖细胞的动员增加了 3 倍以上。硫酸乙酰肝素类似物或 G-CSF/AMD3100/类似物联合动员的造血干细胞在原发性和继发性造血重建致死性照射小鼠方面与 G-CSF/AMD3100 联合动员的造血干细胞同样有效。
这种新型动员剂可以单独或与 G-CSF 和/或 AMD3100 联合应用动员大量造血干细胞，这些造血干细胞能够维持长期造血。这些结果加强了硫酸乙酰肝素在维持造血干细胞在骨髓中的保留作用，并支持使用基于硫酸乙酰肝素的小糖药物与 G-CSF 和 AMD3100 联合应用，以改善高造血干细胞动员，特别是在人类治疗中的应用前景。
