Department of Pathology, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, Texas 77030, USA.
Stem Cells Dev. 2010 Sep;19(9):1289-96. doi: 10.1089/scd.2010.0010.
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.
已有大量文献证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方面发挥着关键作用。随着对骨髓瘤干细胞（起始）存在的概念不断发展，我们旨在专门研究 BMSC 在体外和体内对骨髓瘤干细胞生长的支持作用。BMSC 系源自骨髓瘤或对照患者（骨髓瘤或对照 BMSC）。通过 Hoechst 染料染色鉴定“侧群”（SP）来识别 RPMI 8226 骨髓瘤细胞系中的骨髓瘤干细胞。SP 细胞在骨髓瘤 BMSC 上生长时比在对照 BMSC 上形成更多的集落。此外，当在骨髓瘤 BMSC 上生长时，观察到更多的 SP 细胞百分比。在小鼠模型中，用骨髓瘤 BMSC 接种的 SP 细胞比用对照 BMSC 接种的 SP 细胞生长更快。值得注意的是，与非 SP 细胞相比，SP 细胞显示出更高的 CD184（CXCR4）表达。当 SP 细胞与骨髓瘤 BMSC 共培养时，CD184 的表达进一步增加。CD184(+) SP 细胞比 CD184(-) SP 细胞形成更多的集落。用 AMD 3100 治疗，一种 CD184 的抑制剂，当与骨髓瘤 BMSC 共培养时，减少了 CD184(+) SP 细胞的集落形成。这与骨髓瘤细胞中激活的 CD184 的下游靶标 ERK 的活性降低有关。这些发现表明，骨髓瘤 BMSCs 通过至少部分 CXCR4 信号通路创建了一个支持骨髓瘤干细胞的微环境。
