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Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

ABSTRACT: Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

PROVIDER: PRJNA512232 | ENA |

REPOSITORIES: ENA

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Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts from a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed transcriptional changes and disease-associated cellular dysfunction, including activation of the NF-kB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient’s iPSCs. Importantly, the abnormal upregulation of NF-kB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the disease mechanisms of CADASIL and developing treatment strategies for this disease.

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UHRF1-mediated epigenetic regulation of smooth muscle cell modulates development of vascular pathologies

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Human induced pluripotent stem cells derived from a sporadic Alzheimer's disease patient

Project description:Induced pluripotent stem cell (iPSC) disease models have been generated for a number of diseases, and some have shown their potential utilization for pathological and drug toxicological evaluations. We have generated two hiPSC clones from a non-familial Alzheimerâs patient (AD-iPSCs), which expressed typical undifferentiated markers and fulfilled standard pluripotency assays. Genome-wide microarray analysis revealed that AD-iPSCs are highly similar to control hiPSCs and hESCs, albeit with some noticeable differences in several genes: DNAJC15, GRPR, NAIP and SNORD116-18. Several other biomarkers were differentially expressed in AD-iPSC clones, which were implicated in memory impairment and AD. Furthermore, well characterized familial AD-associated genes (APP, PSEN1, PSEN2) and non-familial (A2M, APOE, GAP43, MAOA, MPO, PLAT, PLAU, SORL1, SNCA) exhibited different expression patterns but were largely reset upon reprogramming into a pluripotent state. Overall, hiPSCs can be good candidates for AD modeling and may represent an in vitro alternative to studying disease mechanisms and drug discovery/toxicology studies. Fibroblasts and two hiPSC clones from a non-familial Alzheimerâs patient (AD-iPSCs) were analyzed. For each cell sample, 2-3 biological replicates were obtained.

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