School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK.
BioPharmaceuticals R&D Cell Therapy Department, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Cell Mol Immunol. 2023 Jun;20(6):570-582. doi: 10.1038/s41423-023-01018-9. Epub 2023 Apr 25.
Mesenchymal stromal cells (MSCs) have been extensively tested for the treatment of numerous clinical conditions and have demonstrated good safety but mixed efficacy. Although this outcome can be attributed in part to the heterogeneity of cell preparations, the lack of mechanistic understanding and tools to establish cell pharmacokinetics and pharmacodynamics, as well as the poorly defined criteria for patient stratification, have hampered the design of informative clinical trials. We and others have demonstrated that MSCs can rapidly undergo apoptosis after their infusion. Apoptotic MSCs are phagocytosed by monocytes/macrophages that are then reprogrammed to become anti-inflammatory cells. MSC apoptosis occurs when the cells are injected into patients who harbor activated cytotoxic T or NK cells. Therefore, the activation state of cytotoxic T or NK cells can be used as a biomarker to predict clinical responses to MSC treatment. Building on a large body of preexisting data, an alternative view on the mechanism of MSCs is that an inflammation-dependent MSC secretome is largely responsible for their immunomodulatory activity. We will discuss how these different mechanisms can coexist and are instructed by two different types of MSC "licensing": one that is cell-contact dependent and the second that is mediated by inflammatory cytokines. The varied and complex mechanisms by which MSCs can orchestrate inflammatory responses and how this function is specifically driven by inflammation support a physiological role for tissue stroma in tissue homeostasis, and it acts as a sensor of damage and initiator of tissue repair by reprogramming the inflammatory environment.
间充质基质细胞（MSCs）已经被广泛测试用于治疗许多临床病症，并显示出良好的安全性，但疗效不一。尽管这种结果部分可以归因于细胞制剂的异质性，但缺乏对细胞药代动力学和药效学的机制理解和工具，以及对患者分层的定义不明确，这些都阻碍了有意义的临床试验的设计。我们和其他人已经证明，MSCs 在输注后可以迅速发生细胞凋亡。凋亡的 MSCs 被单核细胞/巨噬细胞吞噬，然后被重新编程成为抗炎细胞。当这些细胞被注射到存在激活的细胞毒性 T 或 NK 细胞的患者中时，MSC 就会发生凋亡。因此，细胞毒性 T 或 NK 细胞的激活状态可以用作预测对 MSC 治疗的临床反应的生物标志物。基于大量已有的数据，关于 MSCs 机制的另一种观点是，炎症依赖性的 MSC 分泌组在很大程度上负责其免疫调节活性。我们将讨论这些不同的机制如何共存，并受两种不同类型的 MSC“许可”的指导：一种是细胞接触依赖性，另一种是由炎症细胞因子介导的。MSCs 可以协调炎症反应的多样且复杂的机制，以及这种功能如何通过炎症特异性地被驱动，支持组织基质在组织稳态中的生理作用，并通过重新编程炎症环境充当损伤的传感器和组织修复的启动者。
