Human iPSC-derived astrocytes transplanted into the mouse brain display three morphological responses to amyloid-β plaques

Background Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. Methods To address these challenges, we established an approach to study human astroglia within the context of the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived glia progenitors into neonatal brains of immunodeficient mice. Results Xenografted (hiPSC)-derived glia progenitors differentiate into astrocytes that integrate functionally within the mouse host brain and mature in a cell-autonomous way retaining human-specific morphologies, unique features and physiological properties. In Alzheimer’s chimeric brains, transplanted hiPSC-derived astrocytes respond to the presence of amyloid plaques with various morphological changes that seem independent of the APOE allelic background. Conclusion In sum, this chimeric model has great potential to analyze the role of patient-derived and genetically modified astroglia in Alzheimer’s disease. ### Competing Interest Statement BDS is a consultant for Eisai. PP, JTCW, AS, SC, MAT, NC, SM, DRT, AMG and AMA declare that they have no competing interests. * 5 M : 5 months of age AD : Alzheimer’s disease Aβ : amyloid-β APOE : Apolipoprotein E CDR : clinical dementia rating DIV : days in vitro EB : embryoid bodies GPCs : glia progenitor cells hiPSCs : human induced pluripotent stem cells IF : immunofluorescence IVC : individually ventilated cages NFT : neurofibrillary tangles NPCs : neural progenitor cells PAM : protospacer adjacent motif PMI : post-mortem interval RFP : red fluorescent protein RT : room temperature SPF : specific pathogen free ssODN : single-strand oligo-deoxynucleotide Tzv : Thiazovivin WT : Wild-type