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J Neuropathol Exp Neurol. 2018 May 1;77(5):353-360. doi: 10.1093/jnen/nly013.

Leptomeninges-Derived Induced Pluripotent Stem Cells and Directly Converted Neurons From Autopsy Cases With Varying Neuropathologic Backgrounds.

Author information

1
Department of Pathology, University of Washington, Seattle, Washington.
2
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington.
3
Department of Medicine, University of Washington, Seattle, Washington.
4
Kaiser Permanente Washington Health Research Institute, University of Washington, Seattle, Washington.
5
Department of Radiology and Neurology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington.

Abstract

Patient-specific stem cell technology from skin and other biopsy sources has transformed in vitro models of neurodegenerative disease, permitting interrogation of the effects of complex human genetics on neurotoxicity. However, the neuropathologic changes that underlie cognitive and behavioral phenotypes can only be determined at autopsy. To better correlate the biology of derived neurons with age-related and neurodegenerative changes, we generated leptomeningeal cell lines from well-characterized research subjects that have undergone comprehensive postmortem neuropathologic examinations. In a series of proof of principle experiments, we reprogrammed autopsy leptomeningeal cell lines to human-induced pluripotent stem cells (hiPSCs) and differentiated these into neurons. We show that leptomeningeal-derived hiPSC lines can be generated from fresh and frozen leptomeninges, are pluripotent, and retain the karyotype of the starting cell population. Additionally, neurons differentiated from these hiPSCs are functional and produce measurable Alzheimer disease-relevant analytes (Aβ and Tau). Finally, we used direct conversion protocols to transdifferentiate leptomeningeal cells to neurons. These resources allow the generation of in vitro models to test mechanistic hypotheses as well as diagnostic and therapeutic strategies in association with neuropathology, clinical and cognitive data, and biomarker studies, aiding in the study of late-onset Alzheimer disease and other age-related neurodegenerative diseases.

PMID:
29474672
PMCID:
PMC6018913
DOI:
10.1093/jnen/nly013
[Indexed for MEDLINE]
Free PMC Article

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