A Bioengineered In Vitro Osteoarthritis Model with Tunable Inflammatory Environments Indicates Context-Dependent Therapeutic Potential of Human Mesenchymal Stem Cells
A Bioengineered In Vitro Osteoarthritis Model with Tunable Inflammatory Environments Indicates Context-Dependent Therapeutic Potential of Human Mesenchymal Stem Cells
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DOI：
10.1007/s40883-019-00109-2
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发表时间：
2019-09-01
影响因子：
2.6
通讯作者：
Hahn, Mariah S.
中科院分区：
文献类型：
--
作者：
Diaz-Rodriguez, Patricia;Erndt-Marino, Josh;Hahn, Mariah S.
最近，关节内注射间充质干细胞（MSC）已被用作早期骨关节炎（OA）的治疗，由于这些细胞的已知免疫调节作用。然而，MSC治疗显示出可变的临床结果。这种疗效的变化可能反映了一系列影响MSC免疫调节能力的因素的相互作用。特别地，关节炎性状态可能影响MSC治疗功效，因为已知抗炎MSC表型依赖于周围环境中促炎细胞因子的水平。为了深入了解关节炎性状态对MSC免疫调节作用的潜在作用，我们首先扩展了先前验证的OA 3D体外模型，以允许可调的炎症条件。然后，我们利用我们扩大的体外OA模型来评估MSC在"高"（高OA）与"低"（低OA）炎症环境中的治疗潜力。将MSC添加到高OA条件下刺激骨关节炎软骨细胞（OAC）显著降低IL-1 β、IFN-γ、MMP-9和MMP-13的产生，并减少巨噬细胞活化。相比之下，在低OA条件下添加MSC增加了OA相关标志物IL-6和IL-8的OAC表达，并在巨噬细胞中诱导伤口愈合样表型。除了这些结果之外，我们还评估了用促炎因子IFN-γ和TNF-α引发的MSC是否可以改善低OA条件下的MSC治疗功效。对于低OA，在引发后没有观察到MSC抗炎作用的改善。这些发现表明炎症环境和MSC "活化"状态在决定MSC免疫调节作用中的关键作用。如果进一步验证，这些知识可能用于调整注射MSC的表型，以改善临床结果。关节组织周围的炎症环境被认为是OA发病机制的基础，因此可能是治疗的关键。这项工作开发了一种控制炎症水平的系统，以评估生物体外的OA治疗。然后，我们使用这个系统来帮助研究间充质干细胞（MSC）的治疗潜力，这是一种新兴但有争议的OA治疗方法。我们的研究结果表明，MSC的功效是依赖于上下文的，并揭示了这些上下文的一些具体情况。如果进一步验证，这些知识可能用于筛选患者和/或定制注射的MSC，改善临床结果。未来工作的描述未来的工作将集中在进一步开发和验证该模型系统，将其用作OA治疗的发现/开发工具。
Recently, intra-articular injections of mesenchymal stem cells (MSCs) have been used as a treatment for early osteoarthritis (OA) due to the known immunomodulatory effects of these cells. However, MSC therapy has shown variable clinical outcomes. This variability in efficacy likely reflects the interplay of a range of factors, which influence MSC immunoregulatory capacity. In particular, joint inflammatory state may impact MSC treatment efficacy due to the known dependence of the anti-inflammatory MSC phenotype on the levels of pro-inflammatory cytokines in the surrounding environment. To gain insight into the potential role of joint inflammatory state on MSC immunomodulatory effects, we first expanded a previously validated 3D in vitro model of OA to allow for tunable inflammatory conditions. We then utilized our expanded in vitro OA model to assess the therapeutic potential of MSCs in "high" (high-OA) versus "low" (low-OA) inflammatory contexts. The addition of MSCs to high-OA conditions stimulated significantly lower production of IL-1 beta, IFN-gamma, MMP-9, and MMP-13 by osteoarthritic chondrocytes (OACs) and reduced macrophage activation. In contrast, the addition of MSCs to low-OA conditions increased OAC expression of OA-related markers IL-6 and IL-8 and induced a wound healing-like phenotype in macrophages. In addition to these results, we also assessed if MSCs primed with pro-inflammatory factors IFN-gamma and TNF-alpha could improve MSC treatment efficacy in low-OA conditions. No improvements in MSC anti-inflammatory effects were observed for low-OA after priming. These findings suggest a key role for the inflammatory environment and MSC "activation" state in determining MSC immunomodulatory effects. If further validated, this knowledge could potentially be used to tailor the phenotype of injected MSCs to improve clinical outcomes. Lay Summary The inflammatory environment surrounding joint tissues is believed to underlie OA pathogenesis and may therefore hold a key to treatment. This work developed a system with control of inflammatory levels to assess OA therapies outside of living organisms. We then used this system to help study the therapeutic potential of mesenchymal stem cells (MSCs), an emergent yet controversial OA treatment. Our results suggest that MSC efficacy is context-dependent and sheds light on some of the specifics of these contexts. If further validated, this knowledge could potentially be used to screen patients and/or tailor the injected MSCs, improving clinical outcomes. Description of Future Work Future work will be focused on the further development and validation of this model system towards its use as a discovery/development tool for OA therapies.