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 ly...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 huma...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. This work extends the therapeutic utility of organoid...Wang et al. engineer mammary organoids as anticancer drug-secreting depots that inhibit post-surgical tumor recurrence and regenerate functional mammary gland tissue. 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...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 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 refra...Two studies 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. uncover a stress-responsive brain-gut-bone marrow axis that drives aging-like dysfunct...Hematopoietic stem cells integrate local and systemic cues to sustain blood homeostasis. In this issue of Cell Stem Cell, Tian et al. 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. demonstrate that temporal control of BMP signaling d...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. 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. now show that human retinal organoids transplanted into the lesion form a chimeric host-g...Restoring vision after complete optic nerve transection has long seemed out of reach. In this issue of Cell Stem Cell, Gong et al. 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.
Osorio-Vasquez V, Zhu J, Lumibao JC
… +35 more, Lande K, Peck KL, Stamp MK, Okhovat SR, Song H, Ogawa S, Kubota CS, Pantazopoulou V, Curtis K, Kuo K, Dai Y, Rock A, Bottomley CR, Thomas EJ, Hsu J, Herrera Morales A, Fowler A, McGriff T, Evensen KG, Williams AE, Larsen S, Abdulla M, Greer P, Gibson J, Downes M, Evans RM, Lowy AM, Whitcomb DC, Zou J, Molinolo A, Oh TG, White RR, Bellin M, Tiriac H, Engle DD
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 th...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...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...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.
Neovascular age-related macular degeneration is a major cause of irreversible blindness, and current therapies do not restore photoreceptors or retinal pigment epithelium (RPE). Human embryonic stem-cell-derived RPE (hES...Neovascular age-related macular degeneration is a major cause of irreversible blindness, and current therapies do not restore photoreceptors or retinal pigment epithelium (RPE). Human embryonic stem-cell-derived RPE (hESC-RPE) transplantation represents a potential regenerative strategy, but immune rejection limits durable engraftment. Here, we combine immune profiling of blood, aqueous humor, and retinal tissue with allogeneic co-cultures and humanized models to define determinants of graft vulnerability and assess a graft-directed intervention. We identify a Th1-skewed, IFN-γ-rich immune milieu across the circulation and eye and show that IFN-γ-JAK1 signaling promotes an immunogenic state in hESC-RPE, marked by increased HLA expression and antigen presentation features. Brief ex vivo conditioning with ruxolitinib attenuates this response while preserving epithelial properties. In humanized retinal degeneration models, conditioned grafts show reduced T/natural killer (NK)-cell infiltration, prolonged survival, and improved visual function without chronic systemic immunosuppression, supporting ex vivo JAK inhibition as a feasible adjunct to RPE cell therapy.
Su L, Sun Q, Zhou Z
… +22 more, Wang R, Wang J, Alvarez JF, Tao B, Das K, Zhou Q, Wang J, Zhang G, Ten Hoeve J, Zhang L, Pan C, Du Q, Allayee H, Liu Z, Savchenko I, Kou S, Wan J, Pellegrini M, Lusis AJ, Graeber T, Li S, Deb A
The kidney possesses a poor ability to robustly regenerate and repair after acute injury. We show that the ectonucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase-1) is robustly expressed in diseased hum...The kidney possesses a poor ability to robustly regenerate and repair after acute injury. We show that the ectonucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase-1) is robustly expressed in diseased human kidneys and strongly correlates with clinical indices of renal dysfunction. Genetic targeting of Enpp1 in mice enhanced renal repair. A humanized monoclonal antibody, targeting human ENPP1 (hENPP1mAb), when administered in humanized mice, led to tubular cell proliferation, enhanced renal glomerular filtration rate, decreased fibrosis, and rescued renal function after kidney injury. hENPP1mAb augmented nucleotide metabolism and cellular energetics, enabling proliferation and rescuing cell cycle arrest. Single-cell transcriptomics demonstrated expanded signatures of effective repair with hENPP1mAb. In a good laboratory practice (GLP)-compliant dose escalation study, hENPP1mAb was found to be non-toxic and highly tolerated in non-human primates. Our findings identify ENPP1 as a central regulator of acute kidney injury and demonstrate the therapeutic benefit of targeting ENPP1 ectonucleotidase activity with a humanized monoclonal antibody.
Sahu SK, Memczak S, Thakurela S
… +17 more, Lu J, Gupta P, Mutukula N, Hirano A, Zhang Y, Hishida T, Kurita M, Wang C, Shao Y, Williams A, Shokhirev M, Tiwari VK, Rodriguez Esteban C, Reddy P, Meissner A, Li M, Izpisua Belmonte JC
Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen ta...Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.
Understanding how cells change state, interact with their neighbors, and organize into tissues requires recording of cellular lineage history in native spatial context. Here, we present SPACE-seq (spatial tracing enabled...Understanding how cells change state, interact with their neighbors, and organize into tissues requires recording of cellular lineage history in native spatial context. Here, we present SPACE-seq (spatial tracing enabled by CRISPR-based barcodes and slide-seq), a versatile platform that integrates CRISPR-based lineage recording with spatial transcriptomics to jointly resolve lineage, cell state, and tissue architecture at near-cellular resolution in situ. Using SPACE-seq, we uncovered intratumor transcriptional diversification among clonally related cells and identified tumor-stroma crosstalk that reciprocally reshapes behaviors of both malignant and stromal populations, which we further experimentally validated. Beyond disease, SPACE-seq revealed a narrow developmental window in which hepatoblast dispersion contributes to spatially confined lineage compartments that prefigure liver lobar architecture. Together, these results highlight the broad applicability and adaptability of SPACE-seq to uncover previously inaccessible principles of cellular organization, lineage dynamics, and tissue patterning.
Principles of developmental biology have inspired efforts for directed differentiation of human pluripotent stem cells (hPSCs), leading to the first generation of organoids that are now well established as models of huma...Principles of developmental biology have inspired efforts for directed differentiation of human pluripotent stem cells (hPSCs), leading to the first generation of organoids that are now well established as models of human development and disease. However, first-generation organoid models were missing many cell types that would be needed to study normal and pathological processes. Here, we discuss how designing next-generation organoids with increased cellular complexity has been possible by better reproducing developmental processes in play during organogenesis in vivo. We focus on recent conceptual and technical advances in reconstructing appropriate cellular diversity in organoids, dissecting the importance of tissue-tissue interactions and specialized cell addition, and how engineering technologies can further enhance our ability to control how cells are brought together to mimic human development in vitro.
The arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) are highly specialized hypothalamic nuclei controlling appetite and energy expenditure. Here, we demonstrate that human VMH and ARC neurons can be generated f...The arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) are highly specialized hypothalamic nuclei controlling appetite and energy expenditure. Here, we demonstrate that human VMH and ARC neurons can be generated from pluripotent stem cells by fine-tuned timing and duration of bone morphogenetic protein (BMP) exposure. We identified SHH/NKX2.1/FGF10/RAX/TBX3 posterior tuberal progenitors as the source of ARC cell types, including agouti-related peptide (AGRP)-, prepronociceptin (PNOC)-, growth-hormone-releasing hormone (GHRH)-, and thyrotropin-releasing hormone (TRH)-expressing neurons and β2-tanycytes. Differentiated ARC cultures showed high transcriptomic similarity to human ARC and responded to energy homeostasis-regulatory peptides including leptin, glucagon-like peptide 1 (GLP-1), ghrelin, and fibroblast growth factor 1 (FGF1). In contrast, anterior tuberal TBX3 progenitors generated VMH-associated neurons expressing NR5A1, SOX14, and GPR149. Strikingly, two transcriptionally distinct pro-opiomelanocortin (POMC) subpopulations emerged from these lineages, mapping spatially to either the ARC (POMC/TBX3/NR5A2) or the VMH (POMC/SOX14/NR5A1). This model provides a cellular platform to study human hypothalamic subtype specification and pathways involved in central appetite regulation.
Cell Stem Cell
· 2026 Jun · PMID 42242188
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In a recent Nature Biotechnology paper, Pablo De Coppi et al. integrate tissue engineering with organ transplantation in a porcine model. They demonstrate that microinjection of autologous myogenic precursors and fibrobl...In a recent Nature Biotechnology paper, Pablo De Coppi et al. integrate tissue engineering with organ transplantation in a porcine model. They demonstrate that microinjection of autologous myogenic precursors and fibroblasts into a decellularized porcine scaffold, followed by bioreactor maturation, yields a graft that functionally integrates with the native esophagus.
Leukemia stem cells exploit cell-intrinsic ketogenesis to suppress ferroptosis and sustain disease propagation. In this issue, Han et al. uncover a β-hydroxybutyrate-epigenetic-lipid remodeling axis that protects stemnes...Leukemia stem cells exploit cell-intrinsic ketogenesis to suppress ferroptosis and sustain disease propagation. In this issue, Han et al. uncover a β-hydroxybutyrate-epigenetic-lipid remodeling axis that protects stemness by restraining ferroptosis, revealing a metabolic vulnerability with therapeutic potential.
Whether new neurons contribute to human cognition in old age remains debated. Recently in Cell Stem Cell, Tosoni et al. show that immature-neuron transcriptional programs persist in the aged dentate gyrus and that their...Whether new neurons contribute to human cognition in old age remains debated. Recently in Cell Stem Cell, Tosoni et al. show that immature-neuron transcriptional programs persist in the aged dentate gyrus and that their molecular state, not simply their abundance, tracks Alzheimer's pathology and cognitive resilience.