Influence of intrathecal delivery of bone marrow-derived mesenchymal stem cells on spinal inflammation and pain hypersensitivity in a rat model of peripheral nerve injury.
Influence of intrathecal delivery of bone marrow-derived mesenchymal stem cells on spinal inflammation and pain hypersensitivity in a rat model of peripheral nerve injury.
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DOI：
10.1186/s12974-014-0157-8
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发表时间：
2014-09-12
影响因子：
9.3
通讯作者：
Hermans E
中科院分区：
文献类型：
--
作者：
Schäfer S;Berger JV;Deumens R;Goursaud S;Hanisch UK;Hermans E
多能间充质干（基质）细胞（MSC）已被认为具有免疫调节特性，当移植到涉及炎症的各种疾病模型中时，支持有益的结果。潜在的机制包括旁分泌因子的分泌和神经营养微环境的建立。为了验证MSC释放可溶性介质可以减轻局部炎症的假设，我们在这里分析了MSC对小胶质细胞活化的影响，以及对神经病理性疼痛的手术大鼠模型中的炎症参数和疼痛行为的影响。我们专注于部分坐骨神经结扎（PSNL）的实验模型，其特征在于在背侧腰髓中的快速和持续的炎症，其中来自坐骨神经的感觉输入被处理。通过鞘内留置导管，将MSC重复移植到鞘内腰椎间隙中。在PSNL后21天内评价动物的机械和热超敏反应。之后，脊髓进行免疫组化分析的小胶质细胞标记离子钙结合适配器分子1（Iba1）和定量的炎症标记物在同侧背角。我们假设在术后第2至4天注射会干扰小胶质细胞的活化，导致促炎细胞因子的产生减少，疼痛行为改善。PSNL诱导的机械异常性疼痛或热痛觉过敏不受MSC移植的影响，脊髓炎症过程基本上不受影响。事实上，对PSNL的早期小胶质细胞反应（特征为腰椎背角中Iba1表达增加）没有显著改变，手术后21天脊髓中的细胞因子水平与注射溶剂的动物相似。在软脑膜附近检测到移植的MSC，但在脊髓实质内不存在。我们的结论是，鞘内给药是不是一个合适的途径来提供细胞治疗急性脊髓炎症，因为它会导致软脑膜内的移植细胞截留。我们认为，PSNL在腰髓中引发的早期炎症反应未能有效地招募MSC或不足以扰乱组织完整性，从而使MSC穿透脊髓实质。
Multipotent mesenchymal stem (stromal) cells (MSCs) have been credited with immunomodulative properties, supporting beneficial outcomes when transplanted into a variety of disease models involving inflammation. Potential mechanisms include the secretion of paracrine factors and the establishment of a neurotrophic microenvironment. To test the hypothesis that MSCs release soluble mediators that can attenuate local inflammation, we here analysed the influence of MSCs on the activation of microglia cells, as well as on inflammatory parameters and pain behaviour in a surgical rat model of neuropathic pain. We focussed on an experimental model of partial sciatic nerve ligation (PSNL), characterised by a rapid and persistent inflammation in the dorsal lumbar spinal cord where sensory inputs from the sciatic nerve are processed. Via indwelling intrathecal catheters, MSCs were repetitively grafted into the intrathecal lumbar space. Animals were evaluated for mechanical and thermal hypersensitivity over a period of 21 days after PSNL. Afterwards, spinal cords were processed for immunohistochemical analysis of the microglial marker ionized calcium-binding adapter molecule 1 (Iba1) and quantification of inflammatory markers in ipsilateral dorsal horns. We hypothesised that injections on postsurgical days 2 to 4 would interfere with microglial activation, leading to a reduced production of pro-inflammatory cytokines and amelioration of pain behaviour. PSNL-induced mechanical allodynia or heat hyperalgesia were not influenced by MSC transplantation, and spinal cord inflammatory processes remained largely unaffected. Indeed, the early microglial response to PSNL characterised by increased Iba1 expression in the lumbar dorsal horn was not significantly altered and cytokine levels in the spinal cord at 21 days after surgery were similar to those found in vehicle-injected animals. Grafted MSCs were detected close to the pia mater, but were absent within the spinal cord parenchyma. We conclude that intrathecal administration is not an appropriate route to deliver cells for treatment of acute spinal cord inflammation as it leads to entrapment of grafted cells within the pia mater. We propose that the early inflammatory response triggered by PSNL in the lumbar spinal cord failed to effectively recruit MSCs or was insufficient to disturb the tissue integrity so as to allow MSCs to penetrate the spinal cord parenchyma.
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