Dataset Information

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.

ABSTRACT:

Background

Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained.

Results

Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder.

Conclusions

Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.

SUBMITTER: Sorek M

PROVIDER: S-EPMC7934477 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.

Sorek Matan M Oweis Walaa W Nissim-Rafinia Malka M Maman Moria M Simon Shahar S Hession Cynthia C CC Adiconis Xian X Simmons Sean K SK Sanjana Neville E NE Shi Xi X Lu Congyi C Pan Jen Q JQ Xu Xiaohong X Pouladi Mahmoud A MA Ellerby Lisa M LM Zhang Feng F Levin Joshua Z JZ Meshorer Eran E

Genome biology 20210304 1

<h4>Background</h4>Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained.<h4>Results</h4>Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precede ...[more]

PMID: 33663567

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Project description:: Present therapies for stroke rest with tissue plasminogen activator (tPA), the sole licensed antithrombotic on the market; however, tPA's effectiveness is limited in that the drug not only must be administered less than 3-5 hours after stroke but often exacerbates blood-brain barrier (BBB) leakage and increases hemorrhagic incidence. A potentially promising therapy for stroke is transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs). To date, the effects of iPSCs on injuries that take place during early stage ischemic stroke have not been well studied. Consequently, we engrafted iPSC-NSCs into the ipsilesional hippocampus, a natural niche of NSCs, at 24 hours after stroke (prior to secondary BBB opening and when inflammatory signature is abundant). At 48 hours after stroke (24 hours after transplant), hiPSC-NSCs had migrated to the stroke lesion and quickly improved neurological function. Transplanted mice showed reduced expression of proinflammatory factors (tumor necrosis factor-?, interleukin 6 [IL-6], IL-1?, monocyte chemotactic protein 1, macrophage inflammatory protein 1?), microglial activation, and adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and attenuated BBB damage. We are the first to report that engrafted hiPSC-NSCs rapidly improved neurological function (less than 24 hours after transplant). Rapid hiPSC-NSC therapeutic activity is mainly due to a bystander effect that elicits reduced inflammation and BBB damage.Clinically, cerebral vessel occlusion is rarely permanent because of spontaneous or thrombolytic therapy-mediated reperfusion. These results have clinical implications indicating a much extended therapeutic window for transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs; 24 hours after stroke as opposed to the 5-hour window with tissue plasminogen activator [tPA]). In addition, there is potential for a synergistic effect by combining hiPSC-NSC transplantation with tPA to attenuate stroke's adverse effects.

Dataset Information

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.

Background

Results

Conclusions

Publications

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.

Similar Datasets

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