Dataset Information

NeuroLINCS Proteomics: Defining human-derived iPSC proteomes and protein signatures of pluripotency.

ABSTRACT: The National Institute of Health (NIH) Library of integrated network-based cellular signatures (LINCS) program is premised on the generation of a publicly available data resource of cell-based biochemical responses or "signatures" to genetic or environmental perturbations. NeuroLINCS uses human inducible pluripotent stem cells (hiPSCs), derived from patients and healthy controls, and differentiated into motor neuron cell cultures. This multi-laboratory effort strives to establish i) robust multi-omic workflows for hiPSC and differentiated neuronal cultures, ii) public annotated data sets and iii) relevant and targetable biological pathways of spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Here, we focus on the proteomics and the quality of the developed workflow of hiPSC lines from 6 individuals, though epigenomics and transcriptomics data are also publicly available. Known and commonly used markers representing 73 proteins were reproducibly quantified with consistent expression levels across all hiPSC lines. Data quality assessments, data levels and metadata of all 6 genetically diverse human iPSCs analysed by DIA-MS are parsable and available as a high-quality resource to the public.

SUBMITTER: Matlock AD

PROVIDER: S-EPMC9834231 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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NeuroLINCS Proteomics: Defining human-derived iPSC proteomes and protein signatures of pluripotency.

Matlock Andrea D AD Vaibhav Vineet V Holewinski Ronald R Venkatraman Vidya V Dardov Victoria V Manalo Danica-Mae DM Shelley Brandon B Ornelas Loren L Banuelos Maria M Mandefro Berhan B Escalante-Chong Renan R Li Jonathan J Finkbeiner Steve S Fraenkel Ernest E Rothstein Jeffrey J Thompson Leslie L Sareen Dhruv D Svendsen Clive N CN Van Eyk Jennifer E JE

Scientific data 20230111 1

The National Institute of Health (NIH) Library of integrated network-based cellular signatures (LINCS) program is premised on the generation of a publicly available data resource of cell-based biochemical responses or "signatures" to genetic or environmental perturbations. NeuroLINCS uses human inducible pluripotent stem cells (hiPSCs), derived from patients and healthy controls, and differentiated into motor neuron cell cultures. This multi-laboratory effort strives to establish i) robust multi ...[more]

PMID: 36631473

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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:Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype-phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may be related to distinct smooth muscle cell (SMC) embryologic lineages. Thus, peripheral blood mononuclear cell (PBMC)-derived induced pluripotent stem cells (iPSC) were differentiated into lateral mesoderm (LM, aortic root) and neural crest (NC, ascending aorta/transverse arch) SMC lineages to model MFS aortic pathology. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomic analysis by tandem mass spectrometry was applied to profile LM and NC iPSC SMCs from four MFS patients and two healthy controls. Analysis revealed 45 proteins with lineage-dependent expression in MFS patients, many of which were specific to diseased samples. Single protein-level data from both iPSC SMCs and primary MFS aortic root aneurysm tissue confirmed elevated integrin αV and reduced MRC2 in clinical disease specimens, validating the iPSC iTRAQ findings. Functionally, iPSC SMCs exhibited defective adhesion to a variety of extracellular matrix proteins, especially laminin-1 and fibronectin, suggesting altered cytoskeleton dynamics. This study defines the aortic embryologic origin-specific proteome in a validated iPSC SMC model to identify novel protein markers associated with MFS aneurysm phenotype. Translating iPSC findings into clinical aortic aneurysm tissue samples highlights the potential for iPSC-based methods to model MFS disease for mechanistic studies and therapeutic discovery in vitro.

Dataset Information

NeuroLINCS Proteomics: Defining human-derived iPSC proteomes and protein signatures of pluripotency.

Publications

NeuroLINCS Proteomics: Defining human-derived iPSC proteomes and protein signatures of pluripotency.

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