Human iPSC-Derived Mononuclear Phagocytes Improve Cognition and Neural Health across Multiple Mouse Models of Aging and Alzheimer's Disease

Young blood or plasma and young bone marrow improves cognitive function in aged animals, though the cell type responsible for these regenerative effects remains unknown. The current study used induced pluripotent stem cells (iPSCs) to assess the potential of mononuclear phagocytes as a therapeutic for age-associated cognitive decline, as iPSCs provide a source of autologous blood cells without the risk of immune rejection or graft vs. host disease. Human iPSCs differentiated into mononuclear phagocytes (iMPs) were administered to aging, genetically immunocompromised NOD scid gamma mice via tail vein injection. Aging mice receiving iMP treatment showed significant improvements in behavioral tasks relying on spatial working memory and on hippocampus-dependent short-term memory. iMP treatment also had significant effects on several key neural health markers. Expression of the synaptic transporter, VGLUT1, was decreased in untreated aging mice, and levels were restored in aging mice treated with iMPs. Aging mice also had increased numbers of astrocytes and microglia, as well as decreased microglial branching, which were all reversed by iMP treatment. Profiling of the plasma via proteomics and the hippocampus via single nuclei RNA sequencing identified several pathways that may mediate the effects of iMPs. snRNA-seq analysis also revealed that iMP treatment increased a subpopulation of hippocampal mossy cells in aging mice. iPSCs offer an autologous therapy and based on a range of benefits, iPSC-derived mononuclear phagocytes are a promising new therapeutic strategy for age-associated declines in cognition and neural health. Single nucleus sequencing of hippocampus region of mice: 1) Mouse hippocampus from young animals treated with vehicle (2 animals); 2) Mouse hippocampus from aging animals treated with vehicle (3 animals); 3) Mouse hippocampus from aging animals treated with iMPs (3 animals)

年轻血液、血浆与年轻骨髓均可改善衰老动物的认知功能，但其介导此类再生效应的具体细胞类型仍未明确。本研究借助诱导多能干细胞（induced pluripotent stem cells, iPSCs）评估单核吞噬细胞（mononuclear phagocytes）用于治疗衰老相关认知衰退的潜力——因iPSCs可提供自体血细胞来源，规避免疫排斥与移植物抗宿主病（graft vs. host disease）风险。将诱导分化自人iPSCs的单核吞噬细胞（iMPs）经尾静脉注射至基因缺陷型免疫缺陷NOD scid gamma衰老小鼠体内。接受iMP治疗的衰老小鼠，在依赖空间工作记忆与海马依赖性短时记忆的行为学实验中表现出显著改善。iMP治疗同时对多项关键神经健康标志物产生显著调控效应。未处理的衰老小鼠突触转运蛋白VGLUT1的表达水平显著下调，而经iMP治疗的衰老小鼠其VGLUT1表达水平可恢复至正常范围。衰老小鼠的星形胶质细胞与小胶质细胞数量增多，且小胶质细胞分支减少，上述病理异常均在iMP治疗后得到完全逆转。通过蛋白质组学对血浆进行组学表征，并借助单细胞核RNA测序（single nuclei RNA sequencing, snRNA-seq）对海马组织进行转录组分析，最终鉴定出数条可能介导iMPs治疗效应的信号通路。单细胞核RNA测序（snRNA-seq）分析还显示，iMP治疗可显著增加衰老小鼠海马苔藓细胞的亚群比例。iPSCs可提供自体治疗方案，结合其多重临床优势，诱导多能干细胞衍生的单核吞噬细胞有望成为治疗衰老相关认知与神经健康衰退的全新候选治疗策略。小鼠海马组织单细胞核测序分组如下：
1) 溶剂处理的年轻小鼠海马组织（2只）；
2) 溶剂处理的衰老小鼠海马组织（3只）；
3) iMP治疗的衰老小鼠海马组织（3只）