Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy.
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy; Neuroscience Intensive Care Unit, Department of Anesthesia and Critical Care, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Exp Neurol. 2022 Nov;357:114199. doi: 10.1016/j.expneurol.2022.114199. Epub 2022 Aug 8.
The severity and long-term consequences of brain damage in traumatic brain injured (TBI) patients urgently calls for better neuroprotective/neuroreparative strategies for this devastating disorder. Mesenchymal stromal cells (MSCs) hold great promise and have been shown to confer neuroprotection in experimental TBI, mainly through paracrine mechanisms via secreted bioactive factors (i.e. secretome), which indicates significant potential for a cell-free neuroprotective approach. The secretome is composed of cytokines, chemokines, growth factors, proteins, lipids, nucleic acids, metabolites, and extracellular vesicles; it may offer advantages over MSCs in terms of delivery, safety, and variability of therapeutic response for brain injury. Immunomodulation by molecular factors secreted by MSCs is considered to be a key mechanism involved in their multi-potential therapeutic effects. Regulated neuroinflammation is required for healthy remodeling of central nervous system during development and adulthood. Moreover, immune cells and their secreted factors can also contribute to tissue repair and neurological recovery following acute brain injury. However, a chronic and maladaptive neuroinflammatory response can exacerbate TBI and contribute to progressive neurodegeneration and long-term neurological impairments. Here, we review the evidence for MSC-derived secretome as a therapy for TBI. Our framework incorporates a detailed analysis of in vitro and in vivo studies investigating the effects of the secretome on clinically relevant neurological and histopathological outcomes. We also describe the activation of immune cells after TBI and the immunomodulatory properties exerted by mediators released in the secretome. We then describe how ageing modifies central and systemic immune responses to TBI and discuss challenges and opportunities of developing secretome based neuroprotective therapies for elderly TBI populations. Finally, strategies aimed at modulating the secretome in order to boost its efficacy for TBI will also be discussed.
脑损伤（TBI）患者的脑损伤严重程度和长期后果迫切需要更好的神经保护/神经修复策略来治疗这种破坏性疾病。间充质基质细胞（MSCs）具有巨大的潜力，已被证明在实验性 TBI 中具有神经保护作用，主要通过旁分泌机制通过分泌的生物活性因子（即分泌组），这表明细胞游离神经保护方法具有很大的潜力。分泌组由细胞因子、趋化因子、生长因子、蛋白质、脂质、核酸、代谢物和细胞外囊泡组成；它可能在递送、安全性和治疗反应的可变性方面优于 MSCs，适用于脑损伤。MSCs 分泌的分子因子的免疫调节被认为是其多潜能治疗作用的关键机制。在发育和成年过程中，中枢神经系统的健康重塑需要受调控的神经炎症。此外，免疫细胞及其分泌的因子也可以促进急性脑损伤后的组织修复和神经恢复。然而，慢性和适应性不良的神经炎症反应会加重 TBI，并导致进行性神经退行性变和长期神经功能障碍。在这里，我们综述了 MSC 衍生的分泌组作为 TBI 治疗方法的证据。我们的框架包括对体外和体内研究的详细分析，这些研究调查了分泌组对临床相关神经和组织病理学结果的影响。我们还描述了 TBI 后免疫细胞的激活以及分泌组中释放的介质所发挥的免疫调节特性。然后，我们描述了衰老如何改变中枢和全身对 TBI 的免疫反应，并讨论了为老年 TBI 人群开发基于分泌组的神经保护疗法的挑战和机遇。最后，还将讨论旨在调节分泌组以提高其对 TBI 疗效的策略。
