• 文献标题:   Leptomeninges-Derived Induced Pluripotent Stem Cells and Directly Converted Neurons From Autopsy Cases With Varying Neuropathologic Backgrounds
  • 文献类型:   Article
  • 作  者:   ROSE SE, FRANKOWSKI H, KNUPP A, BERRY BJ, MARTINEZ R, DINH SQ, BRUNER LT, WILLIS SL, CRANE PK, LARSON EB, GRABOWSKI T, DARVAS M, KEENE CD, YOUNG JE
  • 作者关键词:   alzheimer disease ad, amyloid beta a beta, humaninduced pluripotent stem cells hipscs, leptomeninge, neurodegenerative disease, neuron
  • 出版物名称:   JOURNAL OF NEUROPATHOLOGY EXPERIMENTAL NEUROLOGY
  • ISSN:   0022-3069 EI 1554-6578
  • 通讯作者地址:   Univ Washington
  • 被引频次:   1
  • DOI:   10.1093/jnen/nly013
  • 出版年:   2018

▎ 摘  要

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 (A beta 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.