Ilic Jovana, Koelbl Christoph, Simon Friederike, Wußmann Maximiliane, Ebert Regina, Trivanovic Drenka, Herrmann Marietta
IZKF Group Tissue Regeneration in Musculoskeletal Diseases, University Hospital Wurzburg, Wuerzburg, Germany.
Bernhard-Heine-Centrum for Locomotion Research, Julius-Maximilians-Universitat Wurzburg, Wuerzburg, Germany.
Tissue Eng Part C Methods. 2024 May;30(5):193-205. doi: 10.1089/ten.TEC.2023.0374. Epub 2024 Apr 17.
Multiple myeloma (MM) clones reside in the bone marrow (BM), which plays a role in its survival and development. The interactions between MM and their neighboring mesenchymal stromal cells (MSCs) have been shown to promote MM growth and drug resistance. However, those interactions are often missing or misrepresented in traditional two-dimensional (2D) culture models. Application of novel three-dimensional (3D) models might recapitulate the BM niche more precisely, which will offer new insights into MM progression and survival. Here, we aimed to establish two 3D models, based on MSC spheroids and collagen droplets incorporating both MM cells and MSCs with the goal of replicating the native myeloma context of the BM niche. This approach revealed that although MSCs can spontaneously assemble spheroids with altered metabolic traits, MSC spheroid culture does not support the integration of MM cells. On the contrary, collagen-droplet culture supported the growth of both cell types. In collagen, MSC proliferation was reduced, with the correlating decrease in ATP production and Ki-67 expression, which might resemble conditions, rather than 2D abundance of nutrients and space. MSCs and MMs were distributed homogenously throughout the collagen droplet, with an apparent CXCL12 expression in MSCs. In addition, the response of MM cells to bortezomib was substantially reduced in collagen, indicating the importance of 3D culture in the investigation of myeloma cell behavior, as drug resistance is one of the most pertinent issues in cancer therapy.
多发性骨髓瘤（MM）克隆存在于骨髓（BM）中，骨髓在其存活和发展中发挥作用。MM与其相邻的间充质基质细胞（MSC）之间的相互作用已被证明可促进MM的生长和耐药性。然而，在传统的二维（2D）培养模型中，这些相互作用常常缺失或被错误呈现。新型三维（3D）模型的应用可能会更精确地模拟骨髓微环境，这将为MM的进展和存活提供新的见解。在这里，我们旨在建立两种3D模型，一种基于MSC球体，另一种基于胶原滴，将MM细胞和MSC整合在一起，以复制骨髓微环境的天然骨髓瘤环境。这种方法表明，尽管MSC可以自发组装具有改变的代谢特征的球体，但MSC球体培养不支持MM细胞的整合。相反，胶原滴培养支持两种细胞类型的生长。在胶原中，MSC增殖减少，ATP产生和Ki-67表达相应降低，这可能类似于实际情况，而不是二维培养中丰富的营养和空间。MSC和MM在整个胶原滴中均匀分布，MSC中明显表达CXCL12。此外，在胶原中MM细胞对硼替佐米的反应显著降低，这表明3D培养在研究骨髓瘤细胞行为中的重要性，因为耐药性是癌症治疗中最相关的问题之一。
