Drug Screening and Drug Repurposing Utilizing Pluripotent Stem Cell-Based Disease Model Systems

Pluripotent stem cell biology, encompassing mouse embryonic stem (ES) cells, human embryonic stem (ES) cells, and human induced pluripotent stem cells (iPSCs), provides a powerful framework for investigating how cellular identity, developmental potential, and lineage specification influence disease modeling and drug responses. The capacity of these cells to self-renew and differentiate into diverse tissue-specific cell types enables the study of disease-associated phenotypes in genetically defined, patient-derived, and genome-edited backgrounds. However, differences in pluripotency state, reprogramming history, epigenetic memory, genetic stability, differentiation efficiency, cellular maturity, and culture conditions can substantially affect the properties and reproducibility of derived models. Recent advances in directed differentiation, organoid and three-dimensional culture, genome editing, single-cell profiling, and high-content imaging have improved the characterization of pluripotent stem cell-derived cells and their responses to pharmacological perturbation. Important questions remain regarding how stem cell state and developmental trajectory shape disease phenotypes, how cellular heterogeneity and maturation influence assay outcomes, and how faithfully these models reproduce human tissue biology. Addressing these questions will be essential for developing reproducible and biologically informative platforms for drug screening and repurposing.This Research Topic aims to advance the application of mouse ES cells, human ES cells, and human iPSCs to drug screening and drug repurposing through a cell and developmental biology perspective. It will highlight studies examining the regulation of self-renewal, pluripotency, reprogramming, lineage commitment, differentiation, maturation, and cell–cell interactions in relation to drug activity and therapeutic response. Emphasis will be placed on defining how pluripotent stem cell state, genetic and epigenetic features, disease-associated cellular phenotypes, and differentiation trajectories influence the interpretation and reproducibility of screening results. The Research Topic will also address the development of high-throughput and high-content platforms, organoids, assembloids, spheroids, and other three-dimensional models that preserve key aspects of tissue development and cellular organization. Genome editing, single-cell and multi-omics approaches, advanced imaging, and computational analyses will be considered where they contribute to understanding stem cell biology, cellular heterogeneity, drug mechanisms, and patient-specific responses. By integrating stem cell, developmental, cellular, and pharmacological perspectives, this Research Topic seeks to support the development of physiologically relevant models for therapeutic discovery.To gather further insights into pluripotent stem cell-based strategies for drug development, this Research Topic will focus on mouse ES cells, human ES cells, and human iPSCs, together with their differentiated derivatives, organoids, and three-dimensional models. We welcome articles addressing, but not limited to, the following themes:• Regulation of pluripotency, self-renewal, reprogramming, lineage commitment, and differentiation in relation to drug responses• Generation and cellular characterization of mouse ES, human ES, and human iPSC-derived disease models• Effects of pluripotent stem cell state, epigenetic memory, genetic background, and reprogramming history on model performance• High-throughput and high-content drug screening using pluripotent stem cell-derived cells• Drug repurposing with patient-derived, genome-edited, and isogenic pluripotent stem cell models• Optimization of stem cell maintenance, expansion, differentiation, maturation, and quality control• Cellular heterogeneity, cell–cell interactions, tissue organization, and developmental trajectories in drug-response assays• Pluripotent stem cell-derived organoids, assembloids, spheroids, and other three-dimensional models for therapeutic testing• Genome editing and functional genomics for investigating disease mechanisms and pharmacological responses• Single-cell transcriptomics, proteomics, epigenomics, spatial profiling, and multi-omics of pluripotent stem cell models• Live-cell imaging, phenotypic profiling, automation, and assay miniaturization for scalable screening• Computational, artificial intelligence, and machine-learning approaches that support the analysis of stem cell states and drug responses• Reproducibility, benchmarking, standardization, scalability, and biological validation of pluripotent stem cell-based platformsConflict of Interest statement: Dr. Erkan Kiris is the founder and CEO of a start-up, TiPS Cell Technologies (METU Technopolis, Ankara, Turkey). TiPS focused on developing iPSC-based disease models and small-molecule, gene, and cell therapies for neurological diseases. Topic editors: Erkan Kiris, Ricardo Raul Cevallos Source: https://www.frontiersin.org/research-topics/83505/drug-screening-and-drug-repurposing-utilizing-pluripotent-stem-cell-based-disease-model-systems