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.