A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies

Abstract

SummaryPrimary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.

Cell Type-Specific In Vitro Gene Expression Profiling of Stem Cell-Derived Neural Models

“…Human cortical-enriched organoids (hCO) were made based on the protocol in [ 45 ]. Human iPSC lines obtained from the Tau Consortium cell line collection ( ) (GIH7-C2Δ2B12 (MAPT V337V CRISPR corrected to WT/WT), GIH7-C2Δ2A01 (MAPT V337M/WT), and ND32951A.15Δ1B06 (MAPT V337V Crispr corrected to WT/WT), NeuraCell [ 46 ], Rennselaer NY, USA) were maintained in mTeSRTM1 medium (STEMCELL Technologies, catalog #05851) based on feeder-free culture protocols in six-well plates (Corning, catalog #3506) coated with growth factor-reduced Matrigel (Corning, catalog #356231). At 80–85% confluency, hiPSC colonies were lifted with Accutase (Innovative Cell Technologies, #NC9839010, San Diego, CA, USA), a single cell suspension was created, and cells were resuspended in E8 medium with rho-associated, coiled-coil-containing protein kinase 1 (ROCK) inhibitor, Y-27632 (Tocris, catalog #1254), at 2 million cells/mL.…”

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

“…Human induced pluripotent stem cells (iPSCs) were obtained from the Knight Alzheimer's Disease Research Center at Washington University 76 , the NIH Childhood-onset Schizophrenia study 77 , and the UCI ADRC (SI Methods Table 8). The Icahn School of Medicine at Mount Sinai IRB reviewed the relevant operating protocols as well as this specific study and determined it was exempt from approval.…”

Answer ALS: A Large-Scale Resource for Sporadic and Familial ALS Combining Clinical Data with Multi-Omics Data from Induced Pluripotent Cell Lines

“…The other strong research advantage to such a dataset and living tools is the immediate ability to test for potentially ALS-relevant pathogenic pathways using the participant's own iPSCs/iPSC-derived spinal neurons to test drugs for candidate pathogenic pathways and, importantly, to develop CNS biomarkers from the iPSCs and validate drug target engagement. Libraries of iPSC lines derived from participants with neurological diseases, including Alzheimer's disease and frontotemporal dementia have been growing in the last several years and represent valuable tool to truly examine speci c disease pathways 67,68 . Most of these iPSC libraries are relatively small, including our orginal library of 22 familial ALS iPS cell lines 69 , with a few selected lines for each disease mutation and when appropriate, isogenic controls.…”