Study for the mechanism of hematopoietic regulation by bone marrow microenvironment

骨髓微环境调节造血机制的研究

• 批准号: 11670024
• 负责人: AIZAWA Shin
• 金额: $ 1.34万
• 依托单位: Nihon University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670024/
• 关键词: bone marrow stromal cell; hematopoietic stem cell; apoptosis; cyclic polylactate; hematopoietic microenvironment; hematopoiesis; myelodysplastic syndrome; anaerobic glycolysis; ストローマ細胞

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

正常造血的特征在于造血干细胞与形成其中发生血细胞产生的微环境部分的细胞和分子之间的平衡相互作用。这反过来表明，这种微环境的某些元素的改变可能导致血细胞的异常产生。骨髓基质细胞是骨髓间充质细胞的异质集合，在骨髓培养中作为粘附层生长，是微环境的重要组成部分。本研究从骨髓增生异常综合征（MDS）难治性贫血（RA）患者的骨髓基质细胞中分离培养，观察骨髓基质细胞在体外支持造血细胞增殖和分化功能的异质性。有趣的是，一些MDS患者的基质细胞诱导造血细胞凋亡改变， ...更多信息 2）将含有SV40早期基因的重组腺病毒载体导入MDS RA患者的骨髓基质细胞系LS 801中，建立了克隆的骨髓基质细胞系LS 801。LS 801在共培养体系中诱导造血细胞凋亡。当用0.45μm的Millipore膜将造血细胞与LS 801隔开以防止其粘附时，LS 801诱导造血细胞凋亡的作用被抑制。这些结果表明，LS 801通过产生扩散因子和直接的细胞相互作用诱导造血细胞凋亡。3）从LS 801的培养液中分离到一种超分子寡聚体环状聚乳酸。发现该寡聚体诱导造血细胞的凋亡变化。这种作用的机制尚不清楚，然而，用这种寡聚体处理的造血细胞的糖酵解酶的活性被抑制。这些结果表明，基质细胞对造血细胞的增殖和分化具有刺激和抑制作用。少

项目成果

Shin AIZAWA et al.: "Induction of apoptotic change of hematopoietic cells by cloned stromal cells from MDS patient via direct cellular interactions."Experimental Hematology. 28. 69 (2000)

Shin AIZAWA 等人：“MDS 患者的克隆基质细胞通过直接细胞相互作用诱导造血细胞凋亡变化。”实验血液学。

Shin AIZAWA et al.: "Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34 positive cell proliferation and differentiation in vitro"Leukemia Research. 23. 239-246 (1999)

Shin AIZAWA 等人：“骨髓增生异常综合征难治性贫血的骨髓基质在体外支持正常 CD34 阳性细胞增殖和分化的能力方面存在缺陷”白血病研究。

Aizawa S. et al.: "Establishment of stromal cell line from an MDS RA patient which induced an apoptotic change in hematopoietic and leukemic cells in vitro."Experimental Hematology. 28. 148-155 (2000)

Aizawa S. 等人：“从 MDS RA 患者中建立基质细胞系，在体外诱导造血细胞和白血病细胞发生凋亡变化。”实验血液学。

Aizawa S.et al.: "Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34-positive cell proliferation and differentiation in vitro."Leukemia Research. 23. 239-246 (1999)

Aizawa S.等人：“骨髓增生异常综合征难治性贫血的骨髓基质在体外支持正常 CD34 阳性细胞增殖和分化的能力方面存在缺陷。”白血病研究。

Aizawa S.et al.: "Effects of cyclic polylactate (CPL) on the growth of cloned leukemic cells in vitro."Hematological Oncology. 18. 51-60 (2000)

Aizawa S.等人：“环状聚乳酸 (CPL) 对体外克隆白血病细胞生长的影响。”血液肿瘤学。