Department of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, MN, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
Cell Transplant. 2023 Jan-Dec;32:9636897231164712. doi: 10.1177/09636897231164712.
Alzheimer's disease (AD) is a devastating neurodegenerative disease with limited therapeutic options. Cellular transplantation of healthy exogenic neurons to replace and restore neuronal cell function has previously been explored in AD animal models, yet most of these transplantation methods have utilized primary cell cultures or donor grafts. Blastocyst complementation offers a novel approach to generate a renewable exogenic source of neurons. These exogenic neurons derived from stem cells would develop with the context of the inductive cues within a host, thus recapitulating the neuron-specific characteristics and physiology. AD affects many different cell types including hippocampal neurons and limbic projection neurons, cholinergic nucleus basis and medial septal neurons, noradrenergic locus coeruleus neurons, serotonergic raphe neurons, and limbic and cortical interneurons. Blastocyst complementation can be adapted to generate these specific neuronal cells afflicted by AD pathology, by ablating important cell type and brain region-specific developmental genes. This review discusses the current state of neuronal transplantation to replace specific neural cell types affected by AD, and the developmental biology to identify candidate genes for knockout in embryos for creating niches to generate exogenic neurons blastocyst complementation.
阿尔茨海默病（AD）是一种具有破坏性的神经退行性疾病，治疗选择有限。在 AD 动物模型中，已经探索了将健康的外源性神经元细胞移植以替代和恢复神经元细胞功能，然而这些移植方法大多利用了原代细胞培养物或供体移植物。囊胚互补提供了一种生成可再生外源性神经元来源的新方法。这些源自干细胞的外源性神经元将在宿主内的诱导线索的背景下发育，从而再现神经元特有的特征和生理学。AD 影响许多不同的细胞类型，包括海马神经元和边缘投射神经元、胆碱能核基底和内侧隔神经元、去甲肾上腺素能蓝斑神经元、5-羟色胺能中缝神经元以及边缘和皮质中间神经元。囊胚互补可以通过消融重要的细胞类型和大脑区域特异性发育基因来适应 AD 病理产生的这些特定神经元细胞。本综述讨论了目前用于替代受 AD 影响的特定神经细胞类型的神经元移植的现状，以及发育生物学，以确定胚胎中用于创建外源性神经元囊胚互补的龛位的候选基因敲除。
