Bone Marrow Stromal Cells From Myeloma Patients Support the Growth of Myeloma Stem Cells
Bone Marrow Stromal Cells From Myeloma Patients Support the Growth of Myeloma Stem Cells
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DOI：
10.1089/scd.2010.0010
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发表时间：
2010-09-01
影响因子：
4
通讯作者：
Chang, Chung-Che
中科院分区：
文献类型：
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作者：
Feng, Yongdong;Wen, Jianguo;Chang, Chung-Che
已有文献表明，多发性骨髓瘤患者的骨髓基质细胞(BMSCs)在支持成熟骨髓瘤细胞生长中起着关键作用。随着有关骨髓瘤干细胞(起始)存在的概念的不断发展，我们的目的是专门研究骨髓间充质干细胞在体外和体内对骨髓瘤干细胞生长的支持作用。骨髓间充质干细胞系来源于骨髓瘤或对照患者(骨髓瘤或对照BMSCs)。用Hoechst染色鉴定RPMI8226骨髓瘤细胞系的“侧群”(SP)，从而识别骨髓瘤干细胞。SP细胞在骨髓瘤BMSC上形成的集落比在对照BMSC上形成的多。此外，观察到在骨髓瘤BMSCs上生长的SP细胞的百分比高于对照BMSCs。在小鼠模型中，接种骨髓瘤BMSCs的SP细胞生长速度快于接种对照BMSCs的SP细胞。值得注意的是，与非SP细胞相比，SP细胞CD184(CXCR4)的表达增加。SP细胞与骨髓瘤BMSCs共培养后，CD184的表达进一步增强。CD184(+)SP细胞比CD184(-)SP细胞形成更多的集落。当CD184(+)SP细胞与骨髓瘤BMSCs共培养时，用CD184抑制剂AMD 3100处理可减少CD184(+)SP细胞的集落形成。这与骨髓瘤细胞中激活的CD184下游靶点ERK的活性降低有关。这些发现表明，骨髓瘤BMSCs至少部分地通过CXCR4信号通路为骨髓瘤干细胞创造了支持的微环境。
It has been well documented that bone marrow stromal cells (BMSCs) of multiple myeloma patients play a pivotal role in supporting the growth of mature myeloma cells. With evolving concepts concerning the presence of myeloma stem (initiating) cells, we aimed this investigation to specifically address the supportive role of BMSCs for myeloma stem cell growth in vitro and in vivo. BMSC lines were derived from myeloma or control patients (myeloma or control BMSCs). Myeloma stem cells of the RPMI 8226 myeloma cell line were recognized through the identification of "side populations" (SP) with Hoechst dye staining. SP cells formed more colonies when grown on myeloma BMSC than on control BMSC. Additionally, higher percentages of SP cells were observed when grown on myeloma BMSCs than on control BMSCs. In the mouse model, SP cells inoculated with myeloma BMSCs grew faster than those inoculated with control BMSCs. Of note, SP cells demonstrated an increased expression of CD184 (CXCR4) compared with non-SP cells. The expression of CD184 in SP cells was further increased when they were cultured with myeloma BMSCs. CD184(+) SP cells formed more colonies than CD184(-) SP cells. Treatment with AMD 3100, an inhibitor of CD184, reduced colony formation by CD184(+) SP cells when co-cultured with myeloma BMSCs. This was associated with the decreased activation of ERK, a downstream target of activated CD184, in myeloma cells. These findings indicate that the myeloma BMSCs create a microenvironment supportive of myeloma stem cells via, at least partially, the CXCR4 signaling pathway.