Zhang Fan, Nance Elizabeth, Alnasser Yossef, Kannan Rangaramanujam, Kannan Sujatha
Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
J Neuroinflammation. 2016 Mar 22;13(1):65. doi: 10.1186/s12974-016-0529-3.
Microglial cells have been implicated in neuroinflammation-mediated injury in the brain, including neurodevelopmental disorders such as cerebral palsy (CP) and autism. Pro-inflammatory activation of microglial cells results in the impairment of their neuroprotective functions, leading to an exaggerated, ongoing immune dysregulation that can persist long after the initial insult. We have previously shown that dendrimer-mediated delivery of an anti-inflammatory agent can attenuate inflammation in a rabbit model of maternal inflammation-induced CP and significantly improve the motor phenotype, due to the ability of the dendrimer to selectively localize in activated microglia.
To elucidate the interactions between dendrimers and microglia, we created an organotypic whole-hemisphere brain slice culture model from newborn rabbits with and without exposure to inflammation in utero. We then used this model to analyze the dynamics of microglial migration and their interactions with dendrimers in the presence of neuroinflammation.
Microglial cells in animals with CP had an amoeboid morphology and impaired cell migration, demonstrated by decreased migration distance and velocity when compared to cells in healthy, age-matched controls. However, this decreased migration was associated with a greater, more rapid dendrimer uptake compared to microglial cells from healthy controls.
This study demonstrates that maternal intrauterine inflammation is associated with impaired microglial function and movement in the newborn brain. This microglial impairment may play a role in the development of ongoing brain injury and CP in the offspring. Increased uptake of dendrimers by the "impaired" microglia can be exploited to deliver drugs specifically to these cells and modulate their functions. Host tissue and target cell characteristics are important aspects to be considered in the design and evaluation of targeted dendrimer-based nanotherapeutics for improved and sustained efficacy. This ex vivo model also provides a rapid screening tool for evaluation of the effects of various therapies on microglial function.
小胶质细胞与大脑中神经炎症介导的损伤有关，包括神经发育障碍，如脑瘫（CP）和自闭症。小胶质细胞的促炎激活导致其神经保护功能受损，导致过度且持续的免疫失调，这种失调在初始损伤后很长时间仍会持续。我们之前已经表明，树枝状大分子介导的抗炎剂递送可以减轻母体炎症诱导的CP兔模型中的炎症，并显著改善运动表型，这是因为树枝状大分子能够选择性地定位于活化的小胶质细胞中。
为了阐明树枝状大分子与小胶质细胞之间的相互作用，我们从新生兔创建了一个器官型全脑半球脑片培养模型，这些新生兔在子宫内有或没有暴露于炎症。然后我们使用这个模型来分析在神经炎症存在的情况下小胶质细胞迁移的动态及其与树枝状大分子的相互作用。
与健康的、年龄匹配的对照组细胞相比，患有CP的动物中的小胶质细胞具有阿米巴样形态且细胞迁移受损，表现为迁移距离和速度降低。然而，与健康对照组的小胶质细胞相比，这种迁移减少与更大、更快的树枝状大分子摄取相关。
本研究表明，母体子宫内炎症与新生大脑中小胶质细胞功能和运动受损有关。这种小胶质细胞损伤可能在后代持续性脑损伤和CP的发展中起作用。“受损”小胶质细胞对树枝状大分子摄取的增加可用于将药物特异性递送至这些细胞并调节其功能。宿主组织和靶细胞特征是设计和评估基于树枝状大分子的靶向纳米疗法以提高和持续疗效时需要考虑的重要方面。这个离体模型还为评估各种疗法对小胶质细胞功能的影响提供了一种快速筛选工具。
