Recent advancements in stem cell differentiation and engineering have highlighted the intricate mechanisms that govern cellular fate and tissue development. Yaman et al. explored the dynamics of human axial morphogenesis by generating organoids that exhibit anteroposterior symmetry breaking, revealing that signaling gradients drive segmentation clock waves essential for proper axial elongation and somitogenesis (ref: Yaman doi.org/10.1016/j.cell.2022.12.042/). Joung et al. contributed to this field by mapping transcription factor (TF) profiles to reference cell types, validating candidate TFs that can induce diverse cell types across all three germ layers, thereby accelerating cellular engineering efforts (ref: Joung doi.org/10.1016/j.cell.2022.11.026/). In a complementary study, Álvarez et al. addressed the maturation challenges of human induced pluripotent stem cell (hiPSC)-derived neurons by utilizing artificial extracellular matrix scaffolds, which provided the necessary cues for improved neuronal maturation (ref: Álvarez doi.org/10.1016/j.stem.2022.12.010/). Zhu et al. further innovated in this area by employing microfluidic technology to engineer human brain assembloids, facilitating the production of region-specific organoids that can be used for drug discovery and regenerative medicine (ref: Zhu doi.org/10.1002/adma.202210083/). Meanwhile, Dai et al. introduced a high-throughput system called CLASH for efficient knock-in engineering of human T cells, significantly enhancing the scalability of targeted gene editing for therapeutic applications (ref: Dai doi.org/10.1038/s41587-022-01639-x/). Castillo-Azofeifa et al. identified a critical DLG1-ARHGAP31-CDC42 axis necessary for intestinal stem cell responses to fluctuating Wnt signaling, emphasizing the importance of niche signals in stem cell maintenance (ref: Castillo-Azofeifa doi.org/10.1016/j.stem.2022.12.008/). Collectively, these studies underscore the potential of stem cell engineering to advance regenerative medicine and therapeutic strategies.

The application of stem cells in disease modeling has provided significant insights into the mechanisms underlying various pathologies. Liu et al. investigated the role of endogenous retroviruses (ERVs) in aging, demonstrating that HERVK can be activated in senescent cells, leading to the production of retrovirus-like particles that induce senescence in younger cells (ref: Liu doi.org/10.1016/j.cell.2022.12.017/). Bouffi et al. advanced this field by transplanting human intestinal organoids (HIOs) into humanized mice, successfully integrating immune cells and forming structures resembling human intestinal lymphoid follicles, thereby enhancing the understanding of human intestinal-immune interactions (ref: Bouffi doi.org/10.1038/s41587-022-01558-x/). Crivello et al. explored the impact of HLA immunopeptidome divergence on leukemia patient outcomes post-transplantation, highlighting the significance of immunogenicity in hematopoietic cell transplantation (ref: Crivello doi.org/10.1200/JCO.22.01229/). Genchi et al. reported on a phase 1 clinical trial evaluating the safety and feasibility of neural precursor cell transplantation in patients with progressive multiple sclerosis, showing promising results in promoting neuroprotection and remyelination (ref: Genchi doi.org/10.1038/s41591-022-02097-3/). Hong et al. conducted a multicenter trial on an autologous T cell therapy targeting MAGE-A4, demonstrating its potential in treating various solid tumors (ref: Hong doi.org/10.1038/s41591-022-02128-z/). These studies collectively illustrate the transformative potential of stem cell applications in modeling diseases and developing novel therapeutic strategies.

Research on stem cells and aging has revealed critical insights into the biological mechanisms that underlie age-related changes. Yang et al. proposed that the loss of epigenetic information contributes significantly to mammalian aging, demonstrating that DNA repair processes can inadvertently accelerate aging by eroding the epigenetic landscape (ref: Yang doi.org/10.1016/j.cell.2022.12.027/). Miao et al. uncovered a novel role for glucose in regulating mRNA splicing and tissue differentiation through its interaction with RNA-binding proteins, suggesting metabolic factors play a crucial role in stem cell function and aging (ref: Miao doi.org/10.1016/j.cell.2022.12.004/). Wang et al. developed a bioengineered 3D skeletal muscle model that revealed complement 4b as a cell-autonomous mechanism impairing regeneration with aging, providing a platform for studying muscle aging (ref: Wang doi.org/10.1002/adma.202207443/). Zeng et al. demonstrated that fecal microbiota transplantation from young mice could rejuvenate aged hematopoietic stem cells by suppressing inflammation, highlighting the potential of microbiome interventions in combating aging (ref: Zeng doi.org/10.1182/blood.2022017514/). Collectively, these findings emphasize the complex interplay between stem cell biology and aging, opening avenues for therapeutic interventions aimed at age-related decline.

The intersection of immunology and stem cell research has yielded promising advancements in therapeutic strategies for various diseases. Mailankody et al. reported on the phase 1 UNIVERSAL trial, evaluating ALLO-715, an allogeneic CAR T cell therapy targeting BCMA in multiple myeloma patients, which aims to minimize graft-versus-host disease while maintaining therapeutic efficacy (ref: Mailankody doi.org/10.1038/s41591-022-02182-7/). Hong et al. also contributed to this theme with their study on afamitresgene autoleucel, an autologous T cell therapy targeting MAGE-A4, demonstrating its potential in treating relapsed/refractory metastatic solid tumors (ref: Hong doi.org/10.1038/s41591-022-02128-z/). Lehrnbecher et al. provided an updated clinical practice guideline for managing fever and neutropenia in pediatric cancer patients, emphasizing the importance of tailored approaches in immunocompromised populations (ref: Lehrnbecher doi.org/10.1200/JCO.22.02224/). These studies highlight the critical role of stem cells in immunotherapy and the need for continued exploration of their applications in enhancing immune responses against cancer.

The genetic and epigenetic regulation of stem cells is pivotal for maintaining pluripotency and guiding differentiation. Iannone et al. investigated the role of the RNA-binding protein PTBP1 in co-transcriptional splicing, revealing that it regulates the epigenetic status of pluripotent stem cells through its influence on chromatin-associated transcripts (ref: Iannone doi.org/10.1016/j.molcel.2022.12.014/). Nakadai et al. explored the activation pathways for orphan estrogen-related receptors (ERRs), uncovering two distinct mechanisms by which these receptors regulate target gene expression, thereby influencing stem cell maintenance and development (ref: Nakadai doi.org/10.1038/s41422-022-00774-z/). Molitor et al. focused on the RNA-binding protein PURA, demonstrating that its depletion disrupts posttranscriptional gene regulation and affects the formation of P-bodies, which are crucial for RNA processing (ref: Molitor doi.org/10.1093/nar/). These studies collectively enhance our understanding of the intricate regulatory networks that govern stem cell biology and their implications for regenerative medicine.

Therapeutic strategies utilizing stem cells have shown great promise in treating various diseases, particularly in regenerative medicine. Genchi et al. conducted a phase 1 study on the transplantation of neural precursor cells in patients with progressive multiple sclerosis, demonstrating the safety and feasibility of this approach in promoting neuroprotection and remyelination (ref: Genchi doi.org/10.1038/s41591-022-02097-3/). Hong et al. reported on the efficacy of afamitresgene autoleucel, an autologous T cell therapy targeting MAGE-A4, in treating relapsed/refractory metastatic solid tumors, showcasing the potential of engineered T cells in cancer therapy (ref: Hong doi.org/10.1038/s41591-022-02128-z/). Mailankody et al. presented interim results from the UNIVERSAL trial, evaluating ALLO-715, an allogeneic CAR T cell therapy for multiple myeloma, which aims to minimize graft-versus-host disease while providing effective treatment (ref: Mailankody doi.org/10.1038/s41591-022-02182-7/). Additionally, Dai et al. introduced CLASH, a system for high-efficiency knock-in engineering of human T cells, which enhances the scalability of gene editing for therapeutic applications (ref: Dai doi.org/10.1038/s41587-022-01639-x/). These studies collectively illustrate the transformative potential of stem cell-based therapies in addressing unmet medical needs.

Stem cells play a crucial role in cancer research, particularly in understanding tumor biology and developing novel therapies. Hong et al. conducted a multicenter trial on afamitresgene autoleucel, an autologous T cell therapy targeting MAGE-A4, demonstrating its efficacy in treating various solid tumors, including synovial sarcoma and ovarian cancer (ref: Hong doi.org/10.1038/s41591-022-02128-z/). Mailankody et al. reported interim results from the phase 1 UNIVERSAL trial, evaluating ALLO-715, an allogeneic CAR T cell therapy targeting BCMA in relapsed/refractory multiple myeloma, which aims to minimize graft-versus-host disease while maintaining therapeutic efficacy (ref: Mailankody doi.org/10.1038/s41591-022-02182-7/). Genchi et al. also contributed to this theme with their study on neural stem cell transplantation in progressive multiple sclerosis, highlighting the potential of stem cells in promoting neuroprotection and remyelination (ref: Genchi doi.org/10.1038/s41591-022-02097-3/). These findings underscore the importance of stem cells in cancer research and their potential to revolutionize treatment strategies.