Study for the mechanism of hematopoietic regulation by bone marrow microenvironment

正常造血的特点是造血干细胞与细胞和分子之间的平衡相互作用，这些细胞和分子构成了产生血细胞的微环境的一部分。这反过来又表明，这种微环境中某些元素的变化可能会导致血细胞的异常产生。骨髓基质细胞是间充质细胞的异质集合，在骨髓培养中以贴壁层的形式生长，是微环境的重要组成部分。1)从骨髓增生异常综合征(MDS)难治性贫血(RA)患者中分离骨髓基质细胞，观察这些患者在体外支持造血细胞增殖分化的基质细胞功能的异质性。有趣的是，一些骨髓增生异常综合征患者的基质细胞诱导了造血细胞…的凋亡改变。2)将含有SV40早期基因的重组SV40-腺病毒载体导入MDS RA患者体内，建立了克隆的基质细胞系LS801。LS801诱导共培养体系中的造血细胞发生凋亡改变。当造血细胞与LS801共培养时，用0.45μm的微孔膜将其与LS801分离，以防止其附着，LS801诱导造血细胞凋亡的作用被抑制。这些结果表明，LS801通过产生扩散因子(S)和通过直接的细胞相互作用诱导造血细胞发生凋亡。3)从LS801的培养上清液中分离到一种超分子低聚物--环状聚乳酸。这种寡聚体被发现能诱导造血细胞的凋亡改变。这一作用的机制尚不清楚，然而，用该低聚物处理的造血细胞的糖酵解酶活性受到抑制。提示基质细胞对造血细胞的增殖和分化既有促进作用，又有抑制作用。较少

Normal hematopoiesis is characterized by a balanced interplay between hematopoietic stem cells and the cells and molectules that form the portion of the microenvironment in which blood cell production takes place. This in turn suggests that alterations in some of the elements of this microenvironment may result in abnormal production of blood cells. Bone marrow stromal cells, a heterogenous collection of mesenchymal cells that grow as an adherent layer in bone marrow culture, are an essential component of the microenvironment. In this study, the hematopoietic regulatory mechanisms of stromal cells were investigated in vitro.1) Bone marrow stromal cells were obtained from myelodysplastic syndrome (MDS) refractory anemia (RA) patients, and the heterogeneiety of stromal cell function in supporting hematopoietic cell proliferation and differentiation in vitro among these patients were observed. Interestingly, stromal cells from some MDS patients induced an apoptotic change in hematopoietic … More stem cells.2) A cloned stromal cell line (LS801) was establisbed from an MDS RA patient by introducing recombinant SV40-adenovirus vector containing the SV40 early gene. LS801 induced an apoptotic change in hematopoietic cells in a coculture system. When hematopoietic cells were cocultured but kept separate from LS801 by a 0.45μm Millipore membrane to prevent their attachment, the action of LS801 in inducing apoptosis of hematopoietic cells was inhibited. These findings suggest that LS801 induced an apoptotic change of hematopoietic cells by producing diffusible factor(s) and via direct cellular interactions.3) A supramolecular oligomer, cyclic polylactate was isolated from the culture medium of LS801. This oligomer was found to induce apoptotic change in hematopoietic cells. The mechanism responsible for this action remains unclear, however, the activities of glycolytic enzymes of hematopoietic cells treated with this oligomer were suppressed. All these findings suggest that stromal cells possess both stimulatory and inhibitory action for the proliferation and differentiation of hematopoietic cells. Less