Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques

Abstract

Background Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular and functional 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. Results To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. Conclusions In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.

Generation of Human iPSC-Derived Astrocytes with a mature star-shaped phenotype for CNS modeling

“…A star-shaped morphology has been greatly elusive in shorter differentiation protocols [ 31 , 36 ] and is only possible to attain after prolonged differentiation ~ 5 months, as Oksanen al. [ 25 ] documented or when transplanting hiPSC-derived astrocytes in mice [ 82 ]. HiAstrocytes showed a star-like morphology and had more complex morphologies (processes > = 3, 41—69%, line depended, Supplementary Fig.…”

Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models

“…Human iPSC modeling has quickly become a critical complementary tool to animal models for understanding complex CNS disorders ( Preman et al, 2021 ; Rivetti di Val Cervo et al, 2021 ). Efficient protocols to generate the main CNS cell types (neurons, microglia, astrocytes, oligodendrocytes, etc.)…”

“…Over the past years, multiple studies from independent laboratories have demonstrated that hiPSC modeling is a powerful tool for uncovering the role of astrocytes in CNS diseases, including AD ( Oksanen et al, 2017 ; Preman et al, 2021 ; de Leeuw et al, 2022 ), Parkinson’s disease ( di Domenico et al, 2019 ; de Rus Jacquet et al, 2021 ; Ramos-Gonzalez et al, 2021 ; Russ et al, 2021 ; Trudler et al, 2021 ) and amyotrophic lateral sclerosis ( Birger et al, 2019 ; Zhao et al, 2020 ; Szebényi et al, 2021 ; Ziff et al, 2021 ; Giacomelli et al, 2022 ). Developing human models is particularly critical since such diseases cannot be fully recapitulated in animal systems and thus require multiple integrated approaches (i.e., combination of human and animal studies) to understand their pathogenic mechanisms.…”

Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease

“…Notably, a third of putative AD risk genes identified in humans lack adequate mouse orthologs, and of particular importance, the APOE polymorphism does not exist in rodents ( Mancuso et al, 2019 ). As will be described, recent work with hiPSC-based models has underscored that human and rodent glia differ significantly in terms of morphology, function, and gene expression profiles ( Preman et al, 2021 ), particularly in the lack of APOE ε4-driven lipid metabolic dysregulation pathways now generally accepted to contribute to AD ( TCW et al, 2022 ). As such, there is a growing movement in the field to take advantage of hiPSC-based models to examine the fundamental disease mechanisms occurring at the molecular and cellular scales within a genetically human background.…”