The prognosis for heart failure (HF) with preserved ejection fraction (HFpEF) remains poor, with treatment evidence and studies at the human cellular level limited. Here, we aimed to model HFpEF-associated diastolic dysfunction in vitro by generating human engineered heart tissues (hEHTs) using human induced pluripotent stem cells and culturing the tissues under high fatty acid and L-N[G]-nitroarginine methyl ester supplementation. Medium-loaded hEHTs showed a marked reduction in relaxation function while preserving contraction function; secreted high levels of the HF marker, BNP; exhibited abnormal calcium transients; and showed structural and functional features of HF. After treatment with several existing HF drugs, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) improved the decline in relaxation function and contributed to an improvement in the diastolic dysfunction phenotype. This mechanism exhibited an anti-inflammatory effect mediated by the recovery of the eNOS-NO-cGMP-PKG signaling pathway. These findings serve as a basis for elucidating the pathogenesis and mechanisms of improvement in HFpEF.

Bone marrow aging compromises hematopoiesis and immunity, yet whether these processes are modifiable in primates remains unexplored. Here, we map the single-cell transcriptomic landscape of primate bone marrow aging and demonstrate that long-term oral vitamin C (VC) supplementation attenuates selected molecular and progenitor-level decline. Aging drives severe common lymphoid progenitor (CLP) depletion, myeloid-biased hematopoietic stem and progenitor cell (HSPC) output, and anatomical site-specific molecular adaptations. VC administration partially offsets these phenotypes, expanding the CLP pool and rebalancing lineage commitment trajectories. This aligns with a ∼4-year reduction in transcriptomic age estimates, cross-validated by an epigenetic clock. Cell-cell communication analyses revealed that VC remodels intercellular signaling, nominating a VC-responsive, progranulin (GRN)-linked candidate pathway. In parallel, human in vitro assays demonstrate that recombinant progranulin mirrors selected VC-associated molecular actions. Collectively, these findings delineate the molecular architecture of primate bone marrow aging and nominate modifiable pathways for further investigation.

Failures in germline development drive male infertility, but the lack of model systems that recapitulate human spermatogenesis hampers therapeutic development. Here, we develop a system to differentiate human-induced pluripotent stem cells (iPSCs) into primordial germ cell-like cells that self-organize with mouse fetal testicular cells into seminiferous tubule-like structures within a xenogeneic reconstituted testis (xrTestis). Subsequent transplantation of xrTestes into immunodeficient mice results in efficient generation of male germ cells up to meiotic onset, including spermatogonia with evidence of prepachytene PIWI-interacting RNA (piRNA) biogenesis, as well as differentiating spermatogonia and rare preleptotene spermatocytes exhibiting transcriptomic and phenotypic similarities to their in vivo counterparts. As future clinical applications will require testing in non-human primates, we apply a similar strategy to differentiate rhesus iPSCs through fetal germ cell stages into spermatogonia and differentiating spermatogonia. Together, these platforms provide a foundation for studying primate germ cell lineages and represent a step toward in vitro gametogenesis.

Chimeric antigen receptor (CAR) T cell therapy faces challenges, such as tumor relapse due to antigen loss and poor CAR T cell expansion in vivo. Optimal tonic signaling (spontaneous CAR signaling) is crucial for CAR T cell fitness and antitumor function, requiring precise calibration to avoid dysfunction or exhaustion. Although CAR phase separation can enhance CAR clustering and tonic signaling to improve cytotoxicity and antigen sensitivity, constitutively high signaling could lead to potential side effects, including cytokine storm and neuronal toxicity. To overcome this limitation, we developed a drug-inducible phase-separation CAR (iPhase-CAR) system utilizing FDA-approved fulvestrant and an engineered estrogen receptor α (ERα) mutant as the drug-inducible phase-separation (DiPS) module. Incorporating the DiPS module into CARs enables drug-inducible clustering of CARs on T cell membranes. iPhase-CAR T cells demonstrate superior antitumor function. This system provides quantitative, reversible promotion of CAR T effector functions, enabling precise control over therapeutic efficacy only upon administration of the FDA-approved drug.

Chronic stress influences hematopoietic stem cells (HSCs). However, how psychological stress regulates HSC function remains incompletely understood. Here, we show that psychological stress impairs HSC self-renewal and lymphoid differentiation, inducing aging-like phenotypes. Stress suppresses neuronal activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG), leading to HSC dysfunction, whereas chemogenetic activation of these regions restores HSC function. Psychological stress or chemogenetic inhibition of the mPFC and PAG reduces the abundance of L. reuteri in the gut microbiota and lowers spermidine levels. Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs. We further demonstrate that mPFC and PAG activity regulate the intestinal environment through a sympathetic pathway, reducing intestinal mucin levels, L. reuteri abundance, and spermidine levels. These findings identify a brain-gut-bone marrow axis linking psychological stress to aging-like HSC dysfunction through sympathetic regulation of intestinal microbiota and spermidine metabolism.

Despite rapid advances in human stem cell-based embryo model (SCBEM) research, national regulatory frameworks remain limited. On April 1, 2026, Japan implemented revised guidelines extending their scope to encompass human SCBEM research. We examine the revisions, differences from ISSCR guidelines, and practical challenges arising during the international regulatory transition period.

Wang et al. engineer mammary organoids as anticancer drug-secreting depots that inhibit post-surgical tumor recurrence and regenerate functional mammary gland tissue.[1] This work extends the therapeutic utility of organoids beyond tissue reconstruction into living therapeutic depots, establishing a strategy to exploit intrinsic physiological processes of the organoids for therapeutic intervention.

In a long-term follow-up of a phase 1/2 clinical trial, Stuart Forbes and colleagues demonstrate that autologous macrophage therapy improves transplantation-free survival in patients with liver cirrhosis. These findings show the translational value of autologous macrophage-based regenerative therapy for advanced liver diseases.

Two studies[1][,][2] published in the last issue of Cell Stem Cell reveal that leukemic stem cell (LSC) identity in acute myeloid leukemia (AML) encodes both anti-apoptotic dependencies and metabolic survival programs. They reframe LSC-directed therapy: eradication may require combinatorial targeting of BCL-2 family proteins and ferroptosis-suppressive ketogenesis in a cell-state-specific manner.

Hematopoietic stem cells integrate local and systemic cues to sustain blood homeostasis. In this issue of Cell Stem Cell, Tian et al.1 uncover a stress-responsive brain-gut-bone marrow axis that drives aging-like dysfunction of hematopoietic stem cells.

Understanding the cellular diversity of the human hypothalamus has been limited by the lack of accessible models. In this issue of Cell Stem Cell, Abay-Nørgaard et al.[1] demonstrate that temporal control of BMP signaling during human pluripotent stem cell differentiation generates diverse hypothalamic populations, providing a platform to study human hypothalamic development and function.

Restoring vision after complete optic nerve transection has long seemed out of reach. In this issue of Cell Stem Cell, Gong et al.[1] now show that human retinal organoids transplanted into the lesion form a chimeric host-graft bridge capable of supporting partial, graft-dependent visual function in adult rats.

Chronic pancreatitis (CP) affects ∼3 million people worldwide, yet altering the course of the disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 37 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with a high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wild-type CFTR. Clinically available CFTR modulators stabilized mutant or wild-type CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides a comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.

Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the genetic and epigenetic drivers underlying this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis-derived organoids. Integrative RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs. Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5[-] cell generation. This reprogramming is mediated by the direct repression of HNF4A and increased H3K27ac and occurs independently of SOX17. Together, these findings identify GATA6 loss as a central regulator of multilineage plasticity that drives liver metastasis in CRC.

Hematopoietic stem and progenitor cells (HSPCs) respond to infections, inflammation, and regenerative challenges using emergency myelopoiesis (EM) pathways to amplify myeloid cell production. However, it remains unclear how various EM inducers regulate HSPCs using shared or distinct molecular mechanisms. Here, we generate a comprehensive and generalizable cell annotation method (HemaScribe) and a refined quantitative model of hematopoietic differentiation (HemaScape) using single-cell RNA sequencing (scRNA-seq) of murine HSPCs, which we apply to a broad range of EM modalities. We uncover multiple strategies for enhancing myelopoiesis that act at different levels of the HSPC hierarchy and are associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based EM activation module across diverse inflammatory challenges that is conserved in humans and informs outcomes in adult and pediatric acute myeloid leukemia. Our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration that have direct translational applications in disease contexts.