Danielyan Lusine, Beer-Hammer Sandra, Stolzing Alexandra, Schäfer Richard, Siegel Georg, Fabian Claire, Kahle Philipp, Biedermann Tilo, Lourhmati Ali, Buadze Marine, Novakovic Ana, Proksch Barbara, Gleiter Christoph H, Frey William H, Schwab Matthias
Department of Clinical Pharmacology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany.
Cell Transplant. 2014;23 Suppl 1:S123-39. doi: 10.3727/096368914X684970. Epub 2014 Oct 9.
In view of the rapid preclinical development of cell-based therapies for neurodegenerative disorders, traumatic brain injury, and tumors, the safe and efficient delivery and targeting of therapeutic cells to the central nervous system is critical for maintaining therapeutic efficacy and safety in the respective disease models. Our previous data demonstrated therapeutically efficacious and targeted delivery of mesenchymal stem cells (MSCs) to the brain in the rat 6-hydroxydopamine model of Parkinson's disease (PD). The present study examined delivery of bone marrow-derived MSCs, macrophages, and microglia to the brain in a transgenic model of PD [(Thy1)-h[A30P] αS] and an APP/PS1 model of Alzheimer's disease (AD) via intranasal application (INA). INA of microglia in naive BL/6 mice led to targeted and effective delivery of cells to the brain. Quantitative PCR analysis of eGFP DNA showed that the brain contained the highest amount of eGFP-microglia (up to 2.1 × 10(4)) after INA of 1 × 10(6) cells, while the total amount of cells detected in peripheral organs did not exceed 3.4 × 10(3). Seven days after INA, MSCs expressing eGFP were detected in the olfactory bulb (OB), cortex, amygdala, striatum, hippocampus, cerebellum, and brainstem of (Thy1)-h[A30P] αS transgenic mice, showing predominant distribution within the OB and brainstem. INA of eGFP-expressing macrophages in 13-month-old APP/PS1 mice led to delivery of cells to the OB, hippocampus, cortex, and cerebellum. Both MSCs and macrophages contained Iba-1-positive population of small microglia-like cells and Iba-1-negative large rounded cells showing either intracellular amyloid β (macrophages in APP/PS1 model) or α-synuclein [MSCs in (Thy1)-h[A30P] αS model] immunoreactivity. Here, we show, for the first time, intranasal delivery of cells to the brain of transgenic PD and AD mouse models. Additional work is needed to determine the optimal dosage (single treatment regimen or repeated administrations) to achieve functional improvement in these mouse models with intranasal microglia/macrophages and MSCs. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
鉴于基于细胞的疗法在神经退行性疾病、创伤性脑损伤和肿瘤的临床前快速发展，将治疗性细胞安全有效地递送至中枢神经系统对于在相应疾病模型中维持治疗效果和安全性至关重要。我们之前的数据表明，在帕金森病（PD）大鼠6-羟基多巴胺模型中，间充质干细胞（MSC）可有效且靶向性地递送至大脑。本研究通过鼻内给药（INA），检测了骨髓来源的MSC、巨噬细胞和小胶质细胞在PD转基因模型[（Thy1）-h[A30P]αS]和阿尔茨海默病（AD）的APP/PS1模型中向大脑的递送情况。在未处理的BL/6小鼠中，鼻内给予小胶质细胞可实现细胞向大脑的靶向性有效递送。对eGFP DNA的定量PCR分析表明，在鼻内给予1×10⁶个细胞后，大脑中eGFP-小胶质细胞的数量最多（高达2.1×10⁴），而在外周器官中检测到的细胞总数不超过3.4×10³。鼻内给药7天后，在（Thy1）-h[A30P]αS转基因小鼠中的嗅球（OB）、皮质、杏仁核、纹状体、海马体、小脑和脑干中检测到表达eGFP的MSC，显示其主要分布在OB和脑干内。在13月龄的APP/PS1小鼠中鼻内给予表达eGFP的巨噬细胞可使细胞递送至OB、海马体、皮质和小脑。MSC和巨噬细胞均含有Iba-1阳性的小胶质细胞样小细胞群体以及Iba-1阴性的大圆形细胞，后者显示细胞内淀粉样β蛋白（APP/PS1模型中的巨噬细胞）或α-突触核蛋白[（Thy1）-h[A30P]αS模型中的MSC]免疫反应性。在此，我们首次展示了通过鼻内给药将细胞递送至转基因PD和AD小鼠模型的大脑。还需要进一步的工作来确定最佳剂量（单次治疗方案或重复给药），以通过鼻内给予小胶质细胞/巨噬细胞和MSC在这些小鼠模型中实现功能改善。本手稿作为国际神经修复学会（IANR）《细胞移植》特刊的一部分发表。
