Abstract
BackgroundIncreasing 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.ResultsTo 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.ConclusionsIn 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.
Highlights
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
Human cells were identified based on the expression of the tdTomato marker Red fluorescent protein (RFP) and of the human nuclear antigen human Nuclear Antigen antibody (hNuclei)
Assessment of the engraftment capacity revealed considerable variation across cell lines (Fig. S1d): we show here examples of robust engraftment, with RFP+ cells both in clusters as well as integrated individually within the mouse brain (Fig. 1b, c), but these results were variable with often lower engraftment capacity at 5 months after transplantation (Fig. S1c, d)
Summary
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. These models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. (ROS), show mitochondrial dysfunction [16] and enhance the release of neurotransmitters including glutamate, GABA and ATP [17] These morphological, molecular and functional alterations highlight the potential importance of these cells in the pathogenesis and progression of AD. Human astrocytes propagate calcium waves four-fold faster than rodent ones [21,22,23], and human and mouse astrocytes show very different responses when exposed to inflammatory stimuli [24, 25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
