The Management of Data for the Banking, Qualification, and Distribution of Induced Pluripotent Stem Cells: Lessons Learned from the European Bank for Induced Pluripotent Stem Cells.

The European Bank for induced pluripotent Stem Cells (EBiSC) was established in 2014 as a non-profit project for the banking, quality control, and distribution of human iPSC lines for research around the world. EBiSC iPSCs are deposited from diverse laboratories internationally and, hence, a key activity for EBiSC is standardising not only the iPSC lines themselves but also the data associated with them. This includes enabling unique nomenclature for the cells, as well as applying uniformity to the data provided by the cell line generator versus quality control data generated by EBiSC, and providing mechanisms to share personal data in a secure and GDPR-compliant manner. A joint approach implemented by EBiSC and the human pluripotent stem cell registry (hPSCreg®) has provided a solution that enabled hPSCreg® to improve its registration platform for iPSCs and EBiSC to have a pipeline for the import, standardisation, storage, and management of data associated with EBiSC iPSCs. In this work, we describe the experience of cell line data management for iPSC banking throughout the course of EBiSC's development as a central European banking infrastructure and present a model for how this could be implemented by other iPSC repositories to increase the FAIRness of iPSC research globally.

Human pluripotent stem cell registry: Operations, role and current directions.

The human plutiripotent stem cell registry (hPSCreg) is a global database for human embryonic and induced pluripotent stem cells (hESC, hiPSC). The publicly accessible Registry (https://hpscreg.eu) was set up to provide a transparent resource of quality-assessed hPSC lines as well as to increase reproducibility of research and interoperability of data. OBJECTIVES: In this review, we describe the establishment of the Registry and its mission, its development into a knowledgebase for hPSC and the current status of hPSC-focussed databases. The data categories available in hPSCreg are detailed. In addition, sharing and hurdles to data sharing on a global level are described. CONCLUSIONS: An outlook is provided on the establishment of digital representatives of donors using hybrids of data and hPSC-based biological models, and how this can also be used to reposition databases as mediators between donors and researchers.

Integrated Collection of Stem Cell Bank Data, a Data Portal for Standardized Stem Cell Information.

The past decade has witnessed an extremely rapid increase in the number of newly established stem cell lines. However, due to the lack of a standardized format, data exchange among stem cell line resources has been challenging, and no system can search all stem cell lines across resources worldwide. To solve this problem, we have developed the Integrated Collection of Stem Cell Bank data (ICSCB) (http://icscb.stemcellinformatics.org/), the largest database search portal for stem cell line information, based on the standardized data items and terms of the MIACARM framework. Currently, ICSCB can retrieve >16,000 cell lines from four major data resources in Europe, Japan, and the United States. ICSCB is automatically updated to provide the latest cell line information, and its integrative search helps users collect cell line information for over 1,000 diseases, including many rare diseases worldwide, which has been a formidable task, thereby distinguishing itself from other database search portals.

A Manually Curated Database on Clinical Studies Involving Cell Products Derived from Human Pluripotent Stem Cells.

The last 5 years have witnessed a significant increase in the number of clinical studies based on human pluripotent stem cells (hPSCs). In parallel, concern is increasing about the proliferation of unregulated stem cell treatments worldwide. Regulated clinical testing is a de facto standard to establish the safety and efficacy of new cell therapies, yet reliable information on clinical studies involving hPSCs is scattered. Our analysis of a multitude of resources found 54 clinical studies involving several types of hPSCs, which are performed in ten countries. While the majority of those studies is based on human embryonic stem cells (hESCs), clinical studies involving human induced pluripotent stem cells increased more strongly in the past 2 years than the number of hESC-based studies. A publicly accessible database was created using the human pluripotent stem cell registry (https://hpscreg.eu) platform, providing a steadily updated comprehensive overview on hPSC-based clinical studies performed worldwide.

Access to stem cell data and registration of pluripotent cell lines: The Human Pluripotent Stem Cell Registry (hPSCreg).

The value of human pluripotent stem cells (hPSC) in regenerative medicine has yet to reach its full potential. The road from basic research tool to clinically validated PSC-derived cell therapy products is a long and winding one, leading researchers, clinicians, industry and regulators alike into undiscovered territory. All stakeholders must work together to ensure the development of safe and effective cell therapies. Similarly, utilization of hPSC in meaningful and controlled disease modeling and drug screening applications requires information on the quality and suitability of the applied cell lines. Central to these common goals is the complete documentation of hPSC data, including the ethical provenance of the source material, the hPSC line derivation, culture conditions and genetic constitution of the lines. Data surrounding hPSC is scattered amongst diverse sources, including publications, supplemental data, researcher lab books, accredited lab reports, certificates of analyses and public data repositories. Not all of these data sources are publicly accessible nor associated with metadata nor stored in a standard manner, such that data can be easily found and retrieved. The Human Pluripotent Stem Cell Registry (hPSCreg; https://hpscreg.eu/) was started in 2007 to impart provenance and transparency towards hPSC research by registering and collecting standard properties of hPSC lines. In this chapter, we present a short primer on the history of stem cell-based products, summarize the ethical and regulatory issues introduced in the course of working with hPSC-derived products and their associated data, and finally present the Human Pluripotent Stem Cell Registry as a valuable resource for all stakeholders in therapies and disease modeling based on hPSC-derived cells.

Recent Trends in Research with Human Pluripotent Stem Cells: Impact of Research and Use of Cell Lines in Experimental Research and Clinical Trials.

The human pluripotent stem cell (hPSC) research landscape is rapidly evolving. To assess possible novel trends in hPSC usage, we analyzed experimental hPSC research published from 2014 to 2016 and compared our data with those of earlier periods. The number of papers describing experimental work involving hPSCs increased further with clear differences in the scientific impact of publications from different countries. Our results confirm the leading position of US-based hPSC research, although to a lesser degree than observed previously. Our data reveal that research into human induced pluripotent stem cells alone surpassed human embryonic stem cell (hESC) research by 2015 and rapidly grew after that. We also report on continuing and even slightly growing research activities in the hESC field as well as on a generally declining rate of the generation of new hESC lines. An increasing portion of new hESC lines represents disease-specific and clinical-grade cell lines. The previously noted usage of only a few early established hESC lines in the vast majority of scientific work is sustained. We also provide a comprehensive overview on clinical trials on the basis of hPSCs. We find that the vast majority of those trials are based on hESC-derived cell products that were generated from an only limited number of relatively old cell lines.

A Standard Nomenclature for Referencing and Authentication of Pluripotent Stem Cells.

Unambiguous cell line authentication is essential to avoid loss of association between data and cells. The risk for loss of references increases with the rapidity that new human pluripotent stem cell (hPSC) lines are generated, exchanged, and implemented. Ideally, a single name should be used as a generally applied reference for each cell line to access and unify cell-related information across publications, cell banks, cell registries, and databases and to ensure scientific reproducibility. We discuss the needs and requirements for such a unique identifier and implement a standard nomenclature for hPSCs, which can be automatically generated and registered by the human pluripotent stem cell registry (hPSCreg). To avoid ambiguities in PSC-line referencing, we strongly urge publishers to demand registration and use of the standard name when publishing research based on hPSC lines.

Rapid establishment of the European Bank for induced Pluripotent Stem Cells (EBiSC) - the Hot Start experience.

A fast track "Hot Start" process was implemented to launch the European Bank for Induced Pluripotent Stem Cells (EBiSC) to provide early release of a range of established control and disease linked human induced pluripotent stem cell (hiPSC) lines. Established practice amongst consortium members was surveyed to arrive at harmonised and publically accessible Standard Operations Procedures (SOPs) for tissue procurement, bio-sample tracking, iPSC expansion, cryopreservation, qualification and distribution to the research community. These were implemented to create a quality managed foundational collection of lines and associated data made available for distribution. Here we report on the successful outcome of this experience and work flow for banking and facilitating access to an otherwise disparate European resource, with lessons to benefit the international research community. ETOC: The report focuses on the EBiSC experience of rapidly establishing an operational capacity to procure, bank and distribute a foundational collection of established hiPSC lines. It validates the feasibility and defines the challenges of harnessing and integrating the capability and productivity of centres across Europe using commonly available resources currently in the field.

hPSCreg--the human pluripotent stem cell registry.

The human pluripotent stem cell registry (hPSCreg), accessible at http://hpscreg.eu, is a public registry and data portal for human embryonic and induced pluripotent stem cell lines (hESC and hiPSC). Since their first isolation the number of hESC lines has steadily increased to over 3000 and new iPSC lines are generated in a rapidly growing number of laboratories as a result of their potentially broad applicability in biomedicine and drug testing. Many of these lines are deposited in stem cell banks, which are globally established to store tens of thousands of lines from healthy and diseased donors. The Registry provides comprehensive and standardized biological and legal information as well as tools to search and compare information from multiple hPSC sources and hence addresses a translational research need. To facilitate unambiguous identification over different resources, hPSCreg automatically creates a unique standardized name for each cell line registered. In addition to biological information, hPSCreg stores extensive data about ethical standards regarding cell sourcing and conditions for application and privacy protection. hPSCreg is the first global registry that holds both, manually validated scientific and ethical information on hPSC lines, and provides access by means of a user-friendly, mobile-ready web application.

Semantic Body Browser: graphical exploration of an organism and spatially resolved expression data visualization.

UNLABELLED: Advancing technologies generate large amounts of molecular and phenotypic data on cells, tissues and organisms, leading to an ever-growing detail and complexity while information retrieval and analysis becomes increasingly time-consuming. The Semantic Body Browser is a web application for intuitively exploring the body of an organism from the organ to the subcellular level and visualising expression profiles by means of semantically annotated anatomical illustrations. It is used to comprehend biological and medical data related to the different body structures while relying on the strong pattern recognition capabilities of human users. AVAILABILITY AND IMPLEMENTATION: The Semantic Body Browser is a JavaScript web application that is freely available at http://sbb.cellfinder.org. The source code is provided on https://github.com/flekschas/sbb.

CellFinder: a cell data repository.

CellFinder (http://www.cellfinder.org) is a comprehensive one-stop resource for molecular data characterizing mammalian cells in different tissues and in different development stages. It is built from carefully selected data sets stemming from other curated databases and the biomedical literature. To date, CellFinder describes 3394 cell types and 50 951 cell lines. The database currently contains 3055 microscopic and anatomical images, 205 whole-genome expression profiles of 194 cell/tissue types from RNA-seq and microarrays and 553 905 protein expressions for 535 cells/tissues. Text mining of a corpus of >2000 publications followed by manual curation confirmed expression information on ∼900 proteins and genes. CellFinder's data model is capable to seamlessly represent entities from single cells to the organ level, to incorporate mappings between homologous entities in different species and to describe processes of cell development and differentiation. Its ontological backbone currently consists of 204 741 ontology terms incorporated from 10 different ontologies unified under the novel CELDA ontology. CellFinder's web portal allows searching, browsing and comparing the stored data, interactive construction of developmental trees and navigating the partonomic hierarchy of cells and tissues through a unique body browser designed for life scientists and clinicians.

CELDA -- an ontology for the comprehensive representation of cells in complex systems.

BACKGROUND: The need for detailed description and modeling of cells drives the continuous generation of large and diverse datasets. Unfortunately, there exists no systematic and comprehensive way to organize these datasets and their information. CELDA (Cell: Expression, Localization, Development, Anatomy) is a novel ontology for the association of primary experimental data and derived knowledge to various types of cells of organisms. RESULTS: CELDA is a structure that can help to categorize cell types based on species, anatomical localization, subcellular structures, developmental stages and origin. It targets cells in vitro as well as in vivo. Instead of developing a novel ontology from scratch, we carefully designed CELDA in such a way that existing ontologies were integrated as much as possible, and only minimal extensions were performed to cover those classes and areas not present in any existing model. Currently, ten existing ontologies and models are linked to CELDA through the top-level ontology BioTop. Together with 15.439 newly created classes, CELDA contains more than 196.000 classes and 233.670 relationship axioms. CELDA is primarily used as a representational framework for modeling, analyzing and comparing cells within and across species in CellFinder, a web based data repository on cells (http://cellfinder.org). CONCLUSIONS: CELDA can semantically link diverse types of information about cell types. It has been integrated within the research platform CellFinder, where it exemplarily relates cell types from liver and kidney during development on the one hand and anatomical locations in humans on the other, integrating information on all spatial and temporal stages. CELDA is available from the CellFinder website: http://cellfinder.org/about/ontology.

Preliminary evaluation of the CellFinder literature curation pipeline for gene expression in kidney cells and anatomical parts.

Biomedical literature curation is the process of automatically and/or manually deriving knowledge from scientific publications and recording it into specialized databases for structured delivery to users. It is a slow, error-prone, complex, costly and, yet, highly important task. Previous experiences have proven that text mining can assist in its many phases, especially, in triage of relevant documents and extraction of named entities and biological events. Here, we present the curation pipeline of the CellFinder database, a repository of cell research, which includes data derived from literature curation and microarrays to identify cell types, cell lines, organs and so forth, and especially patterns in gene expression. The curation pipeline is based on freely available tools in all text mining steps, as well as the manual validation of extracted data. Preliminary results are presented for a data set of 2376 full texts from which >4500 gene expression events in cell or anatomical part have been extracted. Validation of half of this data resulted in a precision of ~50% of the extracted data, which indicates that we are on the right track with our pipeline for the proposed task. However, evaluation of the methods shows that there is still room for improvement in the named-entity recognition and that a larger and more robust corpus is needed to achieve a better performance for event extraction. Database URL: http://www.cellfinder.org/