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NextGen Consortium: iPS Derived Hepatocytes Study (PhLiPS Study)

ABSTRACT:

The goal of the PhLiPS study is to create a library of induced pluripotent stem cell (iPSC) lines and iPSC-derived hepatocytes of diverse genotypes for use in metabolic profiling and interrogating lipid phenotypes. These cell lines were created as a part of the Next Generation Genetic Association Studies (Next Gen) Program, which was a five-year, $80 million program to investigate functional genetic variation in humans by assessing cellular profiles that are surrogates for disease phenotypes. To achieve this, researchers from multiple institutions across the U.S. were awarded grants to derive iPSC lines from more than 1,500 individuals representing various conditions as well as healthy controls for use in functional genomic ("disease in a dish") research. This extensive panel includes a diverse set of age, gender, and ethnic backgrounds, and therefore will be an invaluable tool for evaluations across demographics. Further enhancing the utility of these cell lines are data sets such as phenotyping, GWAS, genome sequencing, gene expression and -omics analyses (e.g., lipidomic, proteomic, methylomic) that can be matched to the cell lines. The PhLiPS Study focuses on individuals free of cardiovascular disease or with lipoprotein metabolism disorders in the community served by the Hospital of the University of Pennsylvania.

PROVIDER: phs001341 | dbGaP |

SECONDARY ACCESSION(S): PRJNA380849PRJNA380850

REPOSITORIES: dbGaP

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Project description:The National Institute of Health (NIH) Library of integrated network-based cellular signatures (LINCS) program is premised on generation of a publicly available data resource composed of cell-based biochemical responses or “signatures” to genetic or environmental perturbations. The NeuroLINCS center focuses on human induced pluripotent stem cells (iPSCs) derived from patients with motor neuron disease and the relevant differentiated neuronal cell cultures originating from patients and healthy controls. To establish a robust data generation process we strive to provide i) workflows for the generation of various multi-omic and functional assays for iPSC-derived motor and cortical neurons, ii) public annotated data sets and iii) relevant and targetable biological pathways of two motor neuron disorders, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Multi-omic assays are performed on aliquots of the same biological specimen and omic data integration analyses have been performed on both iPSCs and iPSC-derived motor neuron (iMN) cultures (unpublished results) Epigenomics, transcriptomics and proteomics data were collected for iPSC cultures originating from 12 individual human iPSC lines. Although iPSCs do not manifest a neurological disease state, they may be explored for asymptomatic biological defects that could ultimately be involved in disease in the context of neuronal tissues. Here we describe the biological diversity of the proteome among 12 individual genetic backgrounds and multiple cell growth replicates of iPSCs. By first defining aspects of non-disease specific biological and technical variability, true disease specific signatures of each omic assay may be extracted with greater clarity. These experiments are part of the transition of discovery proteomics to large data sets consisting of genetically diverse specimens for whole proteome analyses. Through the NIH LINCS program, the multi-omic data sets generated by NeuroLINCS are a public resource provided in tiers of data levels to enable broad applicability throughout the scientific community. From the DIA-MS proteomic analysis of iPSCs originating from 6 cell lines of district genetic backgrounds, 39 proteins recognized iPSC or embryonic stem cell markers were reproducibly quantified with consistent expression levels across all lines analyzed. Another set of consistently quantified proteins extracted from the analyses are more diverse, with little or no known direct associations to iPSCs. Interestingly, some are associated with cancer in the literature, not surprising in that malignancies are known to transition to a less differentiated, more pluripotent biological state to enable increased cell division and metastasis. Possibly even more interesting, as it is less well studied than cancer is the appearance of iPSC proteins quantified that are associated with oocyte health and fertility. Another sub-category of iPSC quantified proteins maybe considered typical housekeeping proteins of cellular metabolism, cell division and cell structure and morphology though as a public resource to be compared with other human tissue or organ cell types many allow the level of expression or isoform specificity to be unique of iPSCs. The data quality assessments and metadata provided make these DIA-MS analyses of 6 cell lines as iPSCs a rich public resource.

Project description:Background:Port wine birthmark (PWB) is a congenital vascular malformation resulting from developmentally defective endothelial cells (ECs). Developing clinically relevant disease models for PWB studies is currently an unmet need. Objective: Our study aims to generate PWB-derived induced pluripotent stem cells (iPSCs) and iPSC-derived ECs that preserve disease-related phenotypes. Methods: PWB iPSCs were generated by reprogramming lesional dermal fibroblasts and differentiated into ECs. RNA-seq was performed to identify differentially expressed genes (DEGs) and enriched pathways. The functional phenotypes of iPSC-derived ECs were characterized by capillary-like structure (CLS) formation in vitro and Geltrex plug-in assay in vivo. Results: Human PWB and control iPSC lines were generated through reprogramming of dermal fibroblasts by introducing the “Yamanaka factors” (Oct3/4, Sox2, Klf4, c-Myc) into them; the iPSCs were successfully differentiated into ECs. These iPSCs and their derived ECs were validated by expression of a series of stem cell and EC biomarkers, respectively. PWB iPSC-derived ECs showed impaired CLS in vitro with larger perimeters and thicker branches as compared to control iPSC-derived ECs. In the plug-in assay, perfused human vasculature formed by PWB iPSC-derived ECs showed bigger perimeters and greater densities than those formed by control iPSC-derived ECs in severe combined immune deficient (SCID) mice. The transcriptome analysis showed that dysregulated pathways of stem cell differentiation, Hippo, Wnt, and focal adhesion persisted through differentiation of PWB iPSCs to ECs. Functional enrichment analysis showed that Hippo and Wnt pathway-related PWB DEGs are enriched for vasculature development, tube morphology, endothelium development, and EC differentiation. Further, members of the zinc finger (ZNF) gene family were overrepresented among the DEGs in PWB iPSCs. ZNF DEGs confer significant functions in transcriptional regulation, chromatin remodeling, protein ubiquitination, and retinoic acid receptor signaling. Furthermore, NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were dysregulated in PWB ECs as readouts of impaired differentiation. Conclusions: PWB iPSC-derived ECs render a novel and clinically-relevant disease model by retaining pathological phenotypes. Our data demonstrate multiple pathways, such as Hippo and Wnt, NF-kappa B, TNF, MAPK, and cholesterol metabolism, are dysregulated, which may contribute to the development of differentiation-defective ECs in PWB.

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NextGen Consortium: iPS Derived Hepatocytes Study (PhLiPS Study)

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