Department of Radiology, Michigan State University, East Lansing, MI, USA.
Department of Radiology, Michigan State University, East Lansing, MI, USA; Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.
Neuroimage. 2019 Oct 1;199:153-159. doi: 10.1016/j.neuroimage.2019.05.073. Epub 2019 May 29.
The subventricular zone (SVZ) is a neurogenic niche in the mammalian brain, giving rise to migratory neural progenitor cells (NPC). In rodents, it is well-established that neurogenesis decreases with aging. MRI-based cell tracking has been used to measure various aspects of neurogenesis and NPC migration in rodents, yet it has not yet been validated in the context of age-related decrease in neurogenesis. This validation is critical to using these MRI techniques to study changes in neurogenesis that arise in diseases prevalent in aging populations and their combination with advanced cellular therapeutic approaches aiming to combat neurodegeneration. As such, in this work we used MRI-based cell tracking to measure endogenous neurogenesis and cell migration from the SVZ along the rostral migratory stream to the olfactory bulb, for 12 days duration, in rats aged 9 weeks to 2 years old. To enable the specific detection of NPCs by MRI, we injected micron sized particles of iron oxide (MPIOs) into the lateral ventricle to endogenously label cells within the SVZ, which then appeared as hypo-intensive spots within MR images. In vivo MRI data showed that the rate of NPC migration was significantly different between all ages examined, with decreases in the distance traveled and migration rate as age progressed. The total number of MPIO-labeled cells within the olfactory bulb on day 12, was significantly decreased when compared across ages in ex vivo high-resolution scans. We also demonstrate for the first-time, provocative preliminary data suggesting age-dependent MPIO uptake within the dentate gyrus (DG) as well. Histology to identify doublecortin-positive NPCs, verified the decrease in cell labeling as a function of aging, for both regions. The dramatic reduction of NPC labeling within the SVZ observed with MRI, validates the sensitivity of MRI-based cell tracking to neurogenic potential and demonstrates the importance of understanding the impact of age on the relationship of NPC and disease.
脑室下区（SVZ）是哺乳动物大脑中的神经发生龛，产生迁移性神经祖细胞（NPC）。在啮齿动物中，神经发生随年龄增长而减少已得到充分证实。基于 MRI 的细胞示踪已被用于测量啮齿动物神经发生和 NPC 迁移的各个方面，但尚未在神经发生与年龄相关的减少的背景下进行验证。这种验证对于使用这些 MRI 技术来研究在衰老人群中常见的疾病中出现的神经发生变化以及将其与旨在对抗神经退行性变的先进细胞治疗方法相结合至关重要。因此，在这项工作中，我们使用基于 MRI 的细胞示踪来测量源自 SVZ 并沿着嗅球迁移流迁移到嗅球的内源性神经发生和细胞迁移，持续 12 天，在 9 周至 2 岁的大鼠中进行。为了使 MRI 能够特异性地检测 NPC，我们将微米级的氧化铁颗粒（MPIO）注入侧脑室，以将 SVZ 内的细胞内源性标记，然后在 MR 图像中显示为低信号点。体内 MRI 数据显示，所有检查年龄的 NPC 迁移率均存在显著差异，随着年龄的增长，迁移距离和迁移率均降低。与体外高分辨率扫描中的年龄相比，第 12 天嗅球内 MPIO 标记细胞的总数明显减少。我们还首次证明了年龄依赖性的 MPIO 在齿状回（DG）内摄取的数据，这也具有启发性。用于识别双皮质素阳性 NPC 的组织学验证了随着年龄的增长，两个区域的细胞标记减少。MRI 观察到的 SVZ 中 NPC 标记的急剧减少，验证了基于 MRI 的细胞示踪对神经发生潜力的敏感性，并证明了理解年龄对 NPC 和疾病关系的影响的重要性。
