Recent advancements in stem cell biology have highlighted the intricate mechanisms governing cell fate and development. A pivotal study by Kim et al. utilized a pooled CRISPR-Cas9 screen to enhance the survival of human pluripotent stem cell (hPSC)-derived dopamine neurons in vivo, demonstrating that transient TNF-α inhibition can significantly improve engraftment and functional recovery in a preclinical model of Parkinson's disease (ref: Kim doi.org/10.1016/j.cell.2024.05.030/). Linneberg-Agerholm et al. explored the role of the primitive endoderm in mammalian blastocyst formation, revealing its capacity to regenerate a complete blastocyst and maintain developmental plasticity, which is crucial for understanding early embryonic development (ref: Linneberg-Agerholm doi.org/10.1016/j.cell.2024.05.051/). Capdevila et al. identified a novel upper crypt population in the intestine, marked by Fgfbp1, which challenges the prevailing model that Lgr5+ cells are the sole intestinal stem cells, suggesting a more complex hierarchy in intestinal regeneration (ref: Capdevila doi.org/10.1016/j.cell.2024.05.001/). Furthermore, Hyun and Wu discussed the implications of developing human organs via embryo models and chimeras, emphasizing the need for ethical considerations as these technologies advance (ref: Hyun doi.org/10.1016/j.cell.2024.05.028/; Wu doi.org/10.1016/j.cell.2024.05.027/). Foerster's research on oligodendrocyte progenitor cells revealed that their developmental origin significantly influences their function in the adult brain, underscoring the importance of understanding lineage-specific roles in neural health (ref: Foerster doi.org/10.1038/s41593-024-01666-8/). Lastly, Long et al. introduced SpatialGlue, a tool for integrating spatial multi-omics data, which enhances our understanding of cellular and tissue properties in developmental contexts (ref: Long doi.org/10.1038/s41592-024-02316-4/).

The application of stem cells in disease modeling has gained momentum, particularly in understanding and treating complex diseases. Brown et al. introduced CytoSPACE, a method for analyzing spatially resolved cell states, which enhances our understanding of cell-cell interactions in various disease contexts (ref: Brown doi.org/10.1038/s41568-024-00713-7/). Zhang et al. developed Amplification Editing (AE), a genome editing tool that allows for precise DNA duplication at chromosomal scales, which could revolutionize genetic studies and therapeutic approaches (ref: Zhang doi.org/10.1016/j.cell.2024.05.056/). In a clinical trial, Corbacioglu et al. demonstrated that combining irinotecan and temozolomide with dasatinib and rapamycin significantly improved progression-free survival in children with relapsed neuroblastoma, highlighting the potential of targeted therapies in pediatric oncology (ref: Corbacioglu doi.org/10.1016/S1470-2045(24)00202-X/). Jakobsen et al. explored clonal hematopoiesis, revealing that mutations in DNMT3A and TET2 confer a selective advantage to hematopoietic stem cells, which may influence disease progression and response to inflammation (ref: Jakobsen doi.org/10.1016/j.stem.2024.05.010/). Peng et al. identified genetic checkpoints in CAR-NK therapy through in vivo AAV-SB-CRISPR screens, providing insights into enhancing NK cell efficacy against tumors (ref: Peng doi.org/10.1038/s41587-024-02282-4/). Lastly, Crotti et al. evaluated the therapeutic efficacy of mexiletine in long QT syndrome type 2, demonstrating its potential to correct cardiac repolarization abnormalities in patient-derived models (ref: Crotti doi.org/10.1161/CIRCULATIONAHA.124.068959/).

The genomic and epigenetic regulation of stem cells is critical for understanding their pluripotency and differentiation potential. Yamanaka's interview reflects on the transformative impact of his discovery of induced pluripotent stem cells (iPSCs) and the future of iPSC applications in regenerative medicine (ref: Yamanaka doi.org/10.1016/j.cell.2024.05.040/). Garate et al. investigated the relationship between genome organization and gene expression during the transition from naive embryonic stem cells to epiblast stem cells, revealing that genome remodeling plays a significant role in regulating transcription during this critical developmental phase (ref: Garate doi.org/10.1093/nar/). Horváth et al. provided insights into how mini-heterochromatin domains constrain the regulatory impact of SVA transposons, shedding light on their role in human brain development and disease (ref: Horváth doi.org/10.1038/s41594-024-01320-8/). Alfeghaly et al. explored the function of XIST and XACT in X chromosome inactivation during early human development, highlighting the complex interplay of lncRNAs in chromatin dynamics (ref: Alfeghaly doi.org/10.1038/s41594-024-01325-3/). Bharti et al. demonstrated that CD55 trafficking to the nucleus induces cisplatin resistance in ovarian cancer by promoting PRC2 activity and H3K27 trimethylation, linking surface proteins to epigenetic regulation (ref: Bharti doi.org/10.1186/s12943-024-02028-5/). Finally, Haage et al. characterized the inflammatory profiles induced by JAK2-V617F and CALR mutations in neutrophils, providing insights into the epigenetic landscape of myeloproliferative neoplasms (ref: Haage doi.org/10.1186/s13045-024-01562-5/).

Stem cell therapy continues to evolve as a promising avenue for regenerative medicine, with recent studies showcasing innovative applications and methodologies. Lin et al. reported successful long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in rhesus macaques, demonstrating the potential for cardiac regeneration without immunosuppression (ref: Lin doi.org/10.1016/j.stem.2024.05.005/). Zhao et al. developed a dual-layered hydrogel embedded with stem cell-derived nanovesicles to regulate reactive oxygen species (ROS) in burn wound healing, highlighting the importance of dynamic ROS management in tissue regeneration (ref: Zhao doi.org/10.1002/adma.202401369/). Rong et al. introduced a superparamagnetic composite hydrogel scaffold for osteoarthritis regeneration, showing promising results in subchondral bone repair through a meticulously designed scaffold (ref: Rong doi.org/10.1002/adma.202405641/). Limone et al. utilized single-nucleus sequencing to uncover enriched expression of genetic risk factors in extratelencephalic neurons affected by ALS, providing insights into the molecular underpinnings of neurodegeneration (ref: Limone doi.org/10.1038/s43587-024-00640-0/). Tharp et al. examined the role of tumor-associated macrophages in restricting CD8+ T cell infiltration in fibrotic tumor microenvironments, suggesting that targeting macrophage behavior could enhance antitumor immunity (ref: Tharp doi.org/10.1038/s43018-024-00775-4/). Lastly, Dennison et al. identified epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's disease, emphasizing the role of stem cell-derived organoids in understanding disease mechanisms (ref: Dennison doi.org/10.1136/gutjnl-2024-332043/).

The intersection of stem cell research and cancer biology has unveiled critical insights into tumorigenesis and therapeutic strategies. Yeh et al. developed a Bayesian model to analyze T cell clonal selection in graft-versus-host disease (GVHD) post-stem cell transplantation, revealing that microbiota influence T cell expansion, which is pivotal for understanding GVHD mechanisms (ref: Yeh doi.org/10.1016/j.immuni.2024.05.018/). Ramberger et al. provided a comprehensive proteogenomic landscape of multiple myeloma, identifying potential therapeutic targets and enhancing our understanding of disease biology (ref: Ramberger doi.org/10.1038/s43018-024-00784-3/). Kimura et al. analyzed childhood gamma delta T-ALL, identifying LMO2/STAG2 rearrangements as high-risk factors, which could inform treatment strategies for this aggressive leukemia subtype (ref: Kimura doi.org/10.1158/2159-8290.CD-23-1452/). Saurat et al. conducted a genome-wide CRISPR screen to identify neddylation as a regulator of neuronal aging and Alzheimer's disease neurodegeneration, linking stem cell models to age-related pathologies (ref: Saurat doi.org/10.1016/j.stem.2024.06.001/). These studies collectively underscore the importance of understanding stem cell dynamics in cancer progression and treatment response.

The microenvironment plays a crucial role in shaping stem cell behavior and their interactions with surrounding tissues. Wang et al. investigated clonal hematopoiesis driven by DNMT3A mutations, linking these mutations to increased inflammatory bone loss and periodontal disease, thus highlighting the systemic effects of stem cell mutations (ref: Wang doi.org/10.1016/j.cell.2024.05.003/). Zhou et al. developed engineered extracellular vesicles for the targeted reprogramming of cancer-associated fibroblasts in pancreatic cancer, demonstrating how manipulating the tumor microenvironment can enhance therapeutic efficacy (ref: Zhou doi.org/10.1038/s41392-024-01872-7/). Yeh et al. introduced a novel label-free imaging technique for permittivity tensor imaging, allowing for high-resolution 3D imaging of biomolecular orientation and mass, which could facilitate the study of stem cell interactions in their native environments (ref: Yeh doi.org/10.1038/s41592-024-02291-w/). Salcedo et al. led a community effort to benchmark tumor subclonal reconstruction algorithms, emphasizing the importance of understanding tumor heterogeneity and evolution in the context of stem cell-derived tumors (ref: Salcedo doi.org/10.1038/s41587-024-02250-y/). Collectively, these studies illustrate the dynamic interplay between stem cells and their microenvironment, which is critical for both normal development and disease progression.

The ethical and societal implications of stem cell research are increasingly relevant as the field advances. Clark et al. discussed the ISSCR guidelines that navigate the ethical landscape of stem cell and embryo research, emphasizing the need for responsible scientific practices that consider societal values (ref: Clark doi.org/10.1016/j.cell.2024.05.041/). Hyun et al. raised philosophical questions regarding the implications of dynamic models of human development created from stem cells, suggesting that these technologies may challenge traditional notions of individuality and humanity (ref: Hyun doi.org/10.1016/j.cell.2024.05.028/). Yamanaka's reflections on the progress of iPSC technology highlight the balance between scientific innovation and ethical responsibility, as the potential for clinical applications continues to grow (ref: Yamanaka doi.org/10.1016/j.cell.2024.05.040/). These discussions underscore the importance of integrating ethical considerations into the scientific discourse surrounding stem cell research, ensuring that advancements benefit society while respecting moral boundaries.