Recent advancements in stem cell research have significantly enhanced our understanding of neural differentiation and development. Pașca et al. highlight the progress in constructing human neural circuits in vivo through transplantation, emphasizing the potential of this approach to elucidate human brain development and disease mechanisms (ref: Pașca doi.org/10.1016/j.cell.2023.12.008/). Dror et al. delve into the role of XIST in naive human pluripotent stem cells (hPSCs), demonstrating that XIST can spread across the X chromosome to regulate gene expression, thereby challenging previous notions about X chromosome inactivation in these cells (ref: Dror doi.org/10.1016/j.cell.2023.11.033/). Furthermore, Hendriks et al. present a novel method for generating human fetal brain organoids that self-organize and replicate in vivo cellular heterogeneity, providing a valuable model for studying brain development (ref: Hendriks doi.org/10.1016/j.cell.2023.12.012/). In a related study, Hergenreder et al. report on a combined small-molecule treatment that accelerates the maturation of hPSC-derived neurons, addressing the prolonged maturation timeline that complicates their use in modeling neurological diseases (ref: Hergenreder doi.org/10.1038/s41587-023-02031-z/). Additionally, Foltynie et al. explore the scalability of GMP-grade dopaminergic cells for Parkinson's disease therapy, demonstrating the feasibility of large-scale production of these cells (ref: Foltynie doi.org/10.1016/j.stem.2023.12.005/). Atamian et al. introduce human cerebellar organoids that develop functional Purkinje cells, marking a significant step in modeling cerebellar development and disease (ref: Atamian doi.org/10.1016/j.stem.2023.11.013/). Lastly, Li et al. investigate the role of human uterine natural killer cells in trophoblast differentiation, shedding light on early pregnancy mechanisms (ref: Li doi.org/10.1016/j.stem.2023.12.013/). Yang et al. highlight the impact of SARS-CoV-2 on dopaminergic neurons, linking viral infection to cellular senescence and inflammation (ref: Yang doi.org/10.1016/j.stem.2023.12.012/).

The intersection of cancer research and stem cell biology has yielded critical insights into tumor biology and therapeutic strategies. Liu et al. conducted a comprehensive proteogenomic characterization of small cell lung cancer (SCLC), identifying key mutations and prognostic biomarkers such as HMGB3 and CASP10, which could inform subtype-specific therapies (ref: Liu doi.org/10.1016/j.cell.2023.12.004/). In a significant survey, Lezmi et al. found that 22% of human pluripotent stem cell lines harbor cancer-related mutations, predominantly TP53 mutations, emphasizing the need for vigilant monitoring of these mutations in clinical applications (ref: Lezmi doi.org/10.1038/s41587-023-02090-2/). Zhao et al. explored inherited predisposition to blood cancers, identifying CTR9 as a significant gene linked to myeloid malignancies, thus contributing to the understanding of genetic risk factors (ref: Zhao doi.org/10.1016/j.cell.2023.12.016/). Zheng et al. tackled the challenge of acquired drug resistance in colorectal cancer, demonstrating that targeting LGR4 can effectively overcome resistance mechanisms (ref: Zheng doi.org/10.1038/s43018-023-00715-8/). Additionally, Zhao et al. reported on the development of IL-10-expressing CAR T cells that resist dysfunction in solid tumors, presenting a promising strategy to enhance CAR T cell therapy efficacy (ref: Zhao doi.org/10.1038/s41587-023-02060-8/). Kobayashi-Kirschvink et al. introduced a novel Raman microscopy technique for predicting single-cell RNA expression profiles, which could revolutionize cancer research by providing insights into cellular heterogeneity (ref: Kobayashi-Kirschvink doi.org/10.1038/s41587-023-02082-2/). Huang et al. investigated the mechanisms behind TACE refractoriness in hepatocellular carcinoma, identifying key genes that could guide treatment strategies (ref: Huang doi.org/10.5306/wjco.v15.i1.62/).

The development of neural and brain organoids has opened new avenues for studying human brain development and disease. Hendriks et al. demonstrated that human fetal brain organoids can self-organize in vitro, replicating aspects of in vivo cellular heterogeneity and architecture, which is crucial for understanding brain development (ref: Hendriks doi.org/10.1016/j.cell.2023.12.012/). Pașca et al. further advanced this field by discussing the construction of human neural circuits through transplantation, which allows for the study of human neural development and associated disorders in living systems (ref: Pașca doi.org/10.1016/j.cell.2023.12.008/). Hergenreder et al. contributed to this theme by identifying small molecules that accelerate the maturation of hPSC-derived neurons, addressing a significant barrier in using these cells for modeling neurological diseases (ref: Hergenreder doi.org/10.1038/s41587-023-02031-z/). Atamian et al. reported the successful development of human cerebellar organoids that exhibit functional Purkinje cells, providing a model for studying cerebellar development and related disorders (ref: Atamian doi.org/10.1016/j.stem.2023.11.013/). Li et al. explored the role of uterine natural killer cells in trophoblast differentiation, which is vital for successful implantation and pregnancy (ref: Li doi.org/10.1016/j.stem.2023.12.013/). Yang et al. highlighted the effects of SARS-CoV-2 on dopaminergic neurons, linking viral infection to cellular senescence and inflammation, which has implications for understanding COVID-19's neurological impacts (ref: Yang doi.org/10.1016/j.stem.2023.12.012/).

Research on metabolism in stem cells has revealed critical insights into how metabolic pathways influence stem cell function and aging. Zhao et al. identified CTR9 as a significant gene linked to inherited blood cancer predisposition, highlighting the role of transcription elongation in cancer biology (ref: Zhao doi.org/10.1016/j.cell.2023.12.016/). Kim et al. investigated the gut-liver axis and its impact on intestinal stem cell fitness, revealing that liver-derived pigment epithelium-derived factor (PEDF) regulates intestinal stem cell proliferation through Wnt signaling inhibition, thus maintaining gut homeostasis (ref: Kim doi.org/10.1016/j.cell.2024.01.001/). Li et al. also contributed to this theme by examining how human uterine natural killer cells regulate trophoblast differentiation, which is crucial for successful pregnancy and involves metabolic interactions (ref: Li doi.org/10.1016/j.stem.2023.12.013/). Yang et al. discussed the metabolic consequences of SARS-CoV-2 infection on dopaminergic neurons, linking viral infection to cellular senescence and inflammation (ref: Yang doi.org/10.1016/j.stem.2023.12.012/). Kang et al. focused on muscle stem cell aging, demonstrating that restoring intracellular S-adenosylmethionine (SAM) levels can rejuvenate aged muscle stem cells by restoring heterochromatin content and improving regenerative capacity (ref: Kang doi.org/10.1038/s42255-023-00955-z/).

Innovations in stem cell technology are paving the way for new applications in regenerative medicine and disease modeling. Hergenreder et al. developed a high-content imaging assay to accelerate the maturation of hPSC-derived neurons, identifying compounds that enhance neuronal development and function, which is crucial for modeling neurological diseases (ref: Hergenreder doi.org/10.1038/s41587-023-02031-z/). Dai et al. introduced ultrafast bisulfite sequencing (UBS-seq), a technique that significantly reduces the time required to detect 5-methylcytosine in DNA and RNA, thus improving the analysis of epigenetic modifications in stem cells (ref: Dai doi.org/10.1038/s41587-023-02034-w/). Schmok et al. evaluated the role of RNA-binding proteins in alternative splicing, providing insights into how these proteins can be harnessed to manipulate gene expression in stem cells (ref: Schmok doi.org/10.1038/s41587-023-02014-0/). Li et al. also explored the immunological interactions between uterine natural killer cells and trophoblasts, which are critical for successful pregnancy and could inform therapeutic strategies for reproductive health (ref: Li doi.org/10.1016/j.stem.2023.12.013/). Yang et al. highlighted the impact of SARS-CoV-2 on dopaminergic neurons, linking viral infection to cellular senescence and inflammation, which has implications for developing therapies targeting COVID-19-related neurological effects (ref: Yang doi.org/10.1016/j.stem.2023.12.012/).

Epigenetic regulation plays a pivotal role in stem cell biology, influencing differentiation and lineage commitment. Dror et al. investigated the function of XIST in naive human pluripotent stem cells, revealing that XIST can spread across the X chromosome to regulate gene expression, challenging previous assumptions about X chromosome inactivation (ref: Dror doi.org/10.1016/j.cell.2023.11.033/). Schulz et al. examined the role of DNA methylation during embryonic stem cell differentiation, demonstrating that high levels of DNA methylation are critical for the specification of germline and somatic lineages (ref: Schulz doi.org/10.1038/s41594-023-01162-w/). Zhang et al. focused on the auto-suppression of TET dioxygenases, which protects the mouse oocyte genome from oxidative demethylation, highlighting the importance of precise regulation of DNA methylation in development (ref: Zhang doi.org/10.1038/s41594-023-01125-1/). Chervova et al. explored the redundancy of mitotic bookmarking by nuclear receptors in pluripotent cells, suggesting that this redundancy ensures robust gene regulatory network reestablishment after mitosis (ref: Chervova doi.org/10.1038/s41594-023-01195-1/). Li et al. identified TFAP2C and NR5A2 as bipotency activators in totipotent embryos, revealing their roles in regulating both inner cell mass and trophectoderm genes during early development (ref: Li doi.org/10.1038/s41594-023-01199-x/).

Understanding the mechanisms of stem cell aging and its implications for disease is crucial for developing effective therapies. Kang et al. demonstrated that depletion of S-adenosylmethionine (SAM) leads to a loss of heterochromatin in muscle stem cells, contributing to aging. Their findings suggest that restoring SAM levels can rejuvenate aged muscle stem cells and improve regenerative capacity (ref: Kang doi.org/10.1038/s42255-023-00955-z/). Konturek-Ciesla et al. provided evidence that stress-induced gene expression, rather than aging itself, may underlie the transcriptional changes observed in hematopoietic stem cells, challenging traditional views on HSC aging (ref: Konturek-Ciesla doi.org/10.1038/s43587-023-00558-z/). Müller et al. explored the recognition of the SARS-CoV-2 hypermutated BA.2.86 variant by memory T cells, highlighting the adaptability of the immune response in the context of viral evolution (ref: Müller doi.org/10.1016/j.chom.2023.12.010/). Matsui et al. investigated the coordination of pioneer and PRDM transcription factors in maintaining bivalent epigenetic states, which is essential for safeguarding cell fate during differentiation (ref: Matsui doi.org/10.1016/j.molcel.2023.12.007/). These studies collectively underscore the complex interplay between aging, stem cell function, and disease susceptibility.

The interplay between immunology and stem cell biology is critical for understanding both immune responses and regenerative processes. Müller et al. investigated the ability of memory T cells to recognize the SARS-CoV-2 hypermutated BA.2.86 variant, revealing that these T cells can effectively cross-recognize variants, which is crucial for vaccine development and understanding immune memory (ref: Müller doi.org/10.1016/j.chom.2023.12.010/). Valdes et al. introduced a novel expansion microscopy technique that enhances immunostaining of nanostructures in human brain specimens, improving the accessibility of antibodies to epitopes and facilitating better understanding of immune responses in the brain (ref: Valdes doi.org/10.1126/scitranslmed.abo0049/). These advancements highlight the importance of integrating immunological insights into stem cell research, particularly in the context of developing therapies for diseases that involve both immune and stem cell components.