人胎盘间充质干细胞来源的外泌体通过激活内源性神经发生增强脊髓损伤的恢复。
Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis.
机构信息
Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Room 4021, Building E12, Taipa, Macau, SAR, China.
Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
出版信息
Stem Cell Res Ther. 2021 Mar 12;12(1):174. doi: 10.1186/s13287-021-02248-2.
BACKGROUND
Spinal cord injury (SCI) is a debilitating medical condition that can result in the irreversible loss of sensorimotor function. Current therapies fail to provide an effective recovery being crucial to develop more effective approaches. Mesenchymal stem cell (MSC) exosomes have been shown to be able to facilitate axonal growth and act as mediators to regulate neurogenesis and neuroprotection, holding great therapeutic potential in SCI conditions. This study aimed to assess the potential of human placental MSC (hpMSC)-derived exosomes on the functional recovery and reactivation of endogenous neurogenesis in an experimental animal model of SCI and to explore the possible mechanisms involved.
METHODS
The hpMSC-derived exosomes were extracted and transplanted in an experimental animal model of SCI with complete transection of the thoracic segment. Functional recovery, the expression of neural stem/progenitor cell markers and the occurrence of neurogenesis, was assessed 60 days after the treatment. In vitro, neural stem cells (NSCs) were incubated with the isolated exosomes for 24 h, and the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinases (ERK), and cAMP response element binding (CREB) proteins were assessed by western blot.
RESULTS
Exosomes were successfully isolated and purified from hpMSCs. Intravenous injections of these purified exosomes significantly improved the locomotor activity and bladder dysfunction of SCI animals. Further study of the exosomes' therapeutic action revealed that hpMSC-derived exosomes promoted the activation of proliferating endogenous neural stem/progenitor cells as denoted by the significant increase of spinal SOX2GFAP, PAX6Nestin, and SOX1KI67 cells. Moreover, animals treated with exosomes exhibited a significative higher neurogenesis, as indicated by the higher percentage of DCXMAP 2 neurons. In vitro, hpMSC-derived exosomes promoted the proliferation of NSCs and the increase of the phosphorylated levels of MEK, ERK, and CREB.
CONCLUSIONS
This study provides evidence that the use of hpMSC-derived exosomes may constitute a promising therapeutic strategy for the treatment of SCI.
背景
脊髓损伤（SCI）是一种使人衰弱的医疗状况，会导致感觉运动功能的不可逆转丧失。目前的治疗方法未能提供有效的恢复，因此开发更有效的方法至关重要。间充质干细胞（MSC）外泌体已被证明能够促进轴突生长，并作为调节神经发生和神经保护的介质，在 SCI 情况下具有很大的治疗潜力。本研究旨在评估人胎盘 MSC（hpMSC）衍生的外泌体在 SCI 实验动物模型中对功能恢复和内源性神经发生的再激活的潜力，并探讨可能涉及的机制。
方法
从 hpMSC 中提取外泌体，并在胸段完全横断的 SCI 实验动物模型中进行移植。治疗 60 天后，评估功能恢复、神经干细胞/祖细胞标志物的表达和神经发生的发生情况。在体外，将分离的外泌体与神经干细胞（NSCs）孵育 24 小时，通过 Western blot 评估丝裂原活化蛋白激酶激酶（MEK）、细胞外信号调节激酶（ERK）和 cAMP 反应元件结合（CREB）蛋白的磷酸化水平。
结果
成功地从 hpMSCs 中分离和纯化外泌体。这些纯化的外泌体静脉注射显著改善了 SCI 动物的运动活动和膀胱功能障碍。对外泌体治疗作用的进一步研究表明，hpMSC 衍生的外泌体通过显著增加脊髓 SOX2GFAP、PAX6Nestin 和 SOX1KI67 细胞促进增殖的内源性神经干细胞/祖细胞的激活。此外，用外泌体治疗的动物表现出更高的神经发生，如 DCXMAP2 神经元的百分比更高所示。在体外，hpMSC 衍生的外泌体促进 NSCs 的增殖和 MEK、ERK 和 CREB 磷酸化水平的增加。
结论
本研究提供了证据表明，使用 hpMSC 衍生的外泌体可能构成治疗 SCI 的有前途的治疗策略。
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