scholarly journals The Perspectives of Early Diagnosis of Schizophrenia Through the Detection of Epigenomics-Based Biomarkers in iPSC-Derived Neurons

2021 ◽  
Vol 14 ◽  
Author(s):  
Davin Lee ◽  
Jinsoo Seo ◽  
Hae chan Jeong ◽  
Hyosang Lee ◽  
Sung Bae Lee
Keyword(s):  
Early Stage ◽  
Treatment Options ◽  
Induced Pluripotent Stem Cell ◽  
Cell Level ◽  
Timely Manner ◽  
Diagnostic Biomarkers ◽  
Transcriptional Alterations ◽  
Induced Pluripotent ◽  
Biomarker Research ◽  
Early Diagnostic

The lack of early diagnostic biomarkers for schizophrenia greatly limits treatment options that deliver therapeutic agents to affected cells at a timely manner. While previous schizophrenia biomarker research has identified various biological signals that are correlated with certain diseases, their reliability and practicality as an early diagnostic tool remains unclear. In this article, we discuss the use of atypical epigenetic and/or consequent transcriptional alterations (ETAs) as biomarkers of early-stage schizophrenia. Furthermore, we review the viability of discovering and applying these biomarkers through the use of cutting-edge technologies such as human induced pluripotent stem cell (iPSC)-derived neurons, brain models, and single-cell level analyses.

scholarly journals Machine learning identifies abnormal Ca2+ transients in human induced pluripotent stem cell-derived cardiomyocytes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hyun Hwang ◽  
Rui Liu ◽  
Joshua T. Maxwell ◽  
Jingjing Yang ◽  
Chunhui Xu
Keyword(s):  
Machine Learning ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Expert Assessment ◽  
Svm Classifier ◽  
Cell Level ◽  
Human Expert ◽  
Analytical Algorithm ◽  
Induced Pluripotent

Abstract Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide an excellent platform for potential clinical and research applications. Identifying abnormal Ca2+ transients is crucial for evaluating cardiomyocyte function that requires labor-intensive manual effort. Therefore, we develop an analytical pipeline for automatic assessment of Ca2+ transient abnormality, by employing advanced machine learning methods together with an Analytical Algorithm. First, we adapt an existing Analytical Algorithm to identify Ca2+ transient peaks and determine peak abnormality based on quantified peak characteristics. Second, we train a peak-level Support Vector Machine (SVM) classifier by using human-expert assessment of peak abnormality as outcome and profiled peak variables as predictive features. Third, we train another cell-level SVM classifier by using human-expert assessment of cell abnormality as outcome and quantified cell-level variables as predictive features. This cell-level SVM classifier can be used to assess additional Ca2+ transient signals. By applying this pipeline to our Ca2+ transient data, we trained a cell-level SVM classifier using 200 cells as training data, then tested its accuracy in an independent dataset of 54 cells. As a result, we obtained 88% training accuracy and 87% test accuracy. Further, we provide a free R package to implement our pipeline for high-throughput CM Ca2+ analysis.

scholarly journals Dedifferentiation and neuronal repression define familial Alzheimer’s disease

2020 ◽  
Vol 6 (46) ◽  
pp. eaba5933
Author(s):  
Andrew B. Caldwell ◽  
Qing Liu ◽  
Gary P. Schroth ◽  
Douglas R. Galasko ◽  
Shauna H. Yuan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unmet Need ◽  
Induced Pluripotent Stem Cell ◽  
Therapeutic Interventions ◽  
Neuron Models ◽  
Familial Alzheimer’S Disease ◽  
Transcriptional Alterations ◽  
Familial Alzheimer's Disease ◽  
Induced Pluripotent

Identifying the systems-level mechanisms that lead to Alzheimer’s disease, an unmet need, is an essential step toward the development of therapeutics. In this work, we report that the key disease-causative mechanisms, including dedifferentiation and repression of neuronal identity, are triggered by changes in chromatin topology. Here, we generated human induced pluripotent stem cell (hiPSC)–derived neurons from donor patients with early-onset familial Alzheimer’s disease (EOFAD) and used a multiomics approach to mechanistically characterize the modulation of disease-associated gene regulatory programs. We demonstrate that EOFAD neurons dedifferentiate to a precursor-like state with signatures of ectoderm and nonectoderm lineages. RNA-seq, ATAC-seq, and ChIP-seq analysis reveals that transcriptional alterations in the cellular state are orchestrated by changes in histone methylation and chromatin topology. Furthermore, we demonstrate that these mechanisms are observed in EOFAD-patient brains, validating our hiPSC-derived neuron models. The mechanistic endotypes of Alzheimer’s disease uncovered here offer key insights for therapeutic interventions.

scholarly journals Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Francis Grafton ◽  
Jaclyn Ho ◽  
Sara Ranjbarvaziri ◽  
Farshad Farshidfar ◽  
Anastasiia Budan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Deep Learning ◽  
Pluripotent Stem Cell ◽  
Kinase Inhibitors ◽  
Early Stage ◽  
Induced Pluripotent Stem Cell ◽  
Channel Blockers ◽  
Drug Induced ◽  
Induced Pluripotent

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.

scholarly journals Early‐stage development of human induced pluripotent stem cell‐derived neurons

2015 ◽  
Vol 93 (12) ◽  
pp. 1804-1813 ◽  
Author(s):  
Yuki Ohara ◽  
Noriko Koganezawa ◽  
Hiroyuki Yamazaki ◽  
Reiko T. Roppongi ◽  
Kaoru Sato ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Early Stage ◽  
Induced Pluripotent Stem Cell ◽  
Stage Development ◽  
Induced Pluripotent

scholarly journals Exosomes and Hepatocellular Carcinoma: From Bench to Bedside

2019 ◽  
Vol 20 (6) ◽  
pp. 1406 ◽  
Author(s):  
Reina Sasaki ◽  
Tatsuo Kanda ◽  
Osamu Yokosuka ◽  
Naoya Kato ◽  
Shunichi Matsuoka ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Messenger Rna ◽  
Noncoding Rna ◽  
Recent Literature ◽  
Early Stage ◽  
Membrane Vesicle ◽  
Treatment Options ◽  
Diagnostic Biomarkers ◽  
Exosome Biogenesis ◽  
End Stage

As hepatocellular carcinoma (HCC) usually occurs in the background of cirrhosis, which is an end-stage form of liver diseases, treatment options for advanced HCC are limited, due to poor liver function. The exosome is a nanometer-sized membrane vesicle structure that originates from the endosome. Exosome-mediated transfer of proteins, DNAs and various forms of RNA, such as microRNA (miRNA), long noncoding RNA (lncRNA) and messenger RNA (mRNA), contributes to the development of HCC. Exosomes mediate communication between both HCC and non-HCC cells involved in tumor-associated cells, and several molecules are implicated in exosome biogenesis. Exosomes may be potential diagnostic biomarkers for early-stage HCC. Exosomal proteins, miRNAs and lncRNAs could provide new biomarker information for HCC. Exosomes are also potential targets for the treatment of HCC. Notably, further efforts are required in this field. We reviewed recent literature and demonstrated how useful exosomes are for diagnosing patients with HCC, treating patients with HCC and predicting the prognosis of HCC patients.

scholarly journals Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

2018 ◽  
Author(s):  
Dwaipayan Adhya ◽  
Vivek Swarup ◽  
Roland Nagy ◽  
Lucia Dutan ◽  
Carole Shum ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cortical Neurons ◽  
Early Stage ◽  
Induced Pluripotent Stem Cell ◽  
Prenatal Development ◽  
Cellular Level ◽  
Post Mortem ◽  
Type Assignment ◽  
Post Mortem Brain ◽  
Induced Pluripotent

AbstractBackgroundAutism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post-mortem brain studies using adult brains have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from autistic individuals with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism.MethodsIPSCs were generated from 9 unrelated autistic individuals without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing, control, individuals. IPSCs were differentiated towards either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterise iPSCs at different stage of differentiation.ResultsA subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to post-mortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated towards a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors, and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs.ConclusionsTaken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

scholarly journals In situ maturated early-stage human induced pluripotent stem cell-derived cardiomyocytes improve cardiac function by enhancing segmentary contraction in infarcted rats

2021 ◽  
Author(s):  
Diogo Biagi ◽  
Evelyn Thais Fantozzi ◽  
Julliana C Campos-Oliveira ◽  
Marcus Vinicius Naghetini ◽  
Antonio F. Ribeiro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Left Ventricle ◽  
Cardiac Function ◽  
Early Stage ◽  
Alternative Therapy ◽  
Induced Pluripotent Stem Cell ◽  
Preclinical Development ◽  
Ectopic Tissue ◽  
Induced Pluripotent

AbstractThe scant ability of cardiomyocytes to proliferate makes heart regeneration one of the biggest challenges of science. Current therapies do not contemplate heart re-muscularization. In this scenario, stem cell-based approaches have been proposed to overcome the lack of regeneration. We hypothesize PluriCell hiPSC-derived cardiomyocytes (hiPSC-CMs) could enhance rat’s cardiac function after myocardial infarction (MI). Animals were subjected to permanent occlusion of the Left-Ventricle (LV) anterior descending coronary artery (LAD). Seven days after MI, Early-stage hiPSC-CMs were injected intramyocardially. Rats were subjected to Echocardiography pre- and post-treatment. Thirty days after injections, treated rats displayed 6.2% human cardiac grafts, which were characterized molecularly. Left ventricle ejection fraction (LVEF) was improved by 7.8% in cell-injected rats, while placebo controls showed an 18.2% deterioration. Also, cell-treated rats displayed a 92% and 56% increase in radial and circumferential strains, respectively. Human cardiac grafts maturate in situ, preserving proliferation with 10% Ki67 and 3% PHH3 positive nuclei. Grafts were perfused by host vasculature with no evidence for immune rejection nor ectopic tissue formations. Our findings support PluriCell hiPSC-CMs as an alternative therapy to treat MI. The next steps of preclinical development include efficacy studies in large animals on the path to clinical-grade regenerative therapy targeting human patients.

scholarly journals Development and biological characterization of a clinical gene transfer vector for the treatment of MAK-associated retinitis pigmentosa

Gene Therapy ◽  
2021 ◽  
Author(s):  
Budd A. Tucker ◽  
Erin R. Burnight ◽  
Cathryn M. Cranston ◽  
Mallory J. Ulferts ◽  
Meagan A. Luse ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Viral Vectors ◽  
Primary Cilia ◽  
Early Stage ◽  
Phase 1 ◽  
Induced Pluripotent Stem Cell ◽  
Viral Gene ◽  
Augmentation Strategy ◽  
Alu Repeat ◽  
Induced Pluripotent

AbstractBy combining next generation whole exome sequencing and induced pluripotent stem cell (iPSC) technology we found that an Alu repeat inserted in exon 9 of the MAK gene results in a loss of normal MAK transcript and development of human autosomal recessive retinitis pigmentosa (RP). Although a relatively rare cause of disease in the general population, the MAK variant is enriched in individuals of Jewish ancestry. In this population, 1 in 55 individuals are carriers and one third of all cases of recessive RP is caused by this gene. The purpose of this study was to determine if a viral gene augmentation strategy could be used to safely restore functional MAK protein as a step toward a treatment for early stage MAK-associated RP. Patient iPSC-derived photoreceptor precursor cells were generated and transduced with viral vectors containing the MAK transcript. One week after transduction, transcript and protein could be detected via rt-PCR and western blotting respectively. Using patient-derived fibroblast cells and mak knockdown zebra fish we demonstrate that over-expression of the retinal MAK transgene restored the cells ability to regulate primary cilia length. In addition, the visual defect in mak knockdown zebrafish was mitigated via treatment with the retinal MAK transgene. There was no evidence of local or systemic toxicity at 1-month or 3-months following subretinal delivery of clinical grade vector into wild type rats. The findings reported here will help pave the way for initiation of a phase 1 clinical trial for the treatment of patients with MAK-associated RP.

scholarly journals Publicly available hiPSC lines with extreme polygenic risk scores for modeling schizophrenia

2020 ◽  
Author(s):  
Kristina Rehbach ◽  
Hanwen Zhang ◽  
Debamitra Das ◽  
Sara Abdollahi ◽  
Tim Prorok ◽  
...  
Keyword(s):  
Rare Variants ◽  
Treatment Options ◽  
Induced Pluripotent Stem Cell ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Risk Variants ◽  
Important Challenge ◽  
Cell Type Specific ◽  
Induced Pluripotent ◽  
The Impact

ABSTRACTSchizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterize a collection of twelve human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across three independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs, with which we collectively commit to conducting future CRISPR-engineering, in order to facilitate comparison and integration of functional validation studies across the field of psychiatric genetics.

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