Recent studies by Mayama et al. and Akkerman et al. established human adrenal cortex organoids that recapitulate fetal and adult adrenal development, offering unprecedented insight into differentiation pathways and allow...Recent studies by Mayama et al. and Akkerman et al. established human adrenal cortex organoids that recapitulate fetal and adult adrenal development, offering unprecedented insight into differentiation pathways and allowing disease modeling. Though challenges like immature phenotypes and immune rejection will need addressing, they offer great potential for cell-based therapies.
Elucidating cell fate decision-making requires linking lineage history to dynamic phenotypic states. Driven by single-cell sequencing and genome engineering, lineage tracing has evolved from observational studies into a...Elucidating cell fate decision-making requires linking lineage history to dynamic phenotypic states. Driven by single-cell sequencing and genome engineering, lineage tracing has evolved from observational studies into a multidimensional, high-throughput discipline. Here, we synthesize its three methodological pillars: prospective tracking via genetic markers, high-throughput mapping using synthetic barcodes, and retrospective tracing leveraging endogenous natural variants. We survey their integration with multi-omics and spatial profiling, alongside computational approaches to decode cell fates from lineage data. By detailing each approach's trade-offs, we offer a systematic guide for experimental design and highlight emerging frontiers for translating precision clonal analysis into the clinic.
Neointimal hyperplasia, a key pathological feature of many cardiovascular diseases, is driven by vascular smooth muscle cells (SMCs), yet the role of specific SMC subtypes remains unclear. This study identifies a smooth...Neointimal hyperplasia, a key pathological feature of many cardiovascular diseases, is driven by vascular smooth muscle cells (SMCs), yet the role of specific SMC subtypes remains unclear. This study identifies a smooth muscle-derived transient progenitor cell (STPC) population, marked by CD34 expression, which emerges after artery injury. These STPCs exhibit high proliferative capacity and generate the majority of neointimal SMCs. Genetic ablation of STPCs significantly reduces neointimal SMC accumulation and attenuates hyperplasia. Mechanistically, SMC-specific knockdown of DCLK1 markedly suppresses STPC generation and mitigates pathological remodeling. These findings establish STPCs as a critical progenitor population responsible for neointimal hyperplasia, identifying them as a novel therapeutic target for vascular diseases.
Liver cirrhosis is a major contributor to global morbidity and mortality, and transplantation remains the only cure for end-stage disease. Preclinical studies have indicated that macrophage injections reduce inflammation...Liver cirrhosis is a major contributor to global morbidity and mortality, and transplantation remains the only cure for end-stage disease. Preclinical studies have indicated that macrophage injections reduce inflammation, resolve fibrosis, and stimulate liver regeneration. The phase 1/2 Macrophage Therapy for Liver Cirrhosis trial (MATCH01; ISRCTN10368050) demonstrated the safety and potential efficacy of autologous monocyte-derived macrophage therapy in cirrhosis. Following MATCH01, participants were re-enrolled in a long-term follow-up (LTFU) study, extending observation to up to 4 years from randomization. Macrophage-treated patients in MATCH01 phase 2 demonstrated a significantly lower risk of death or transplant within the LTFU period (30.8%) compared with standard medical care (58.3%); macrophage-treated patients had an additional 252 days of restricted mean survival time within the LTFU period. There was no evidence of increased serious adverse events attributable to cell therapy. These results support the continued advancement of macrophage-based regenerative strategies as a promising therapeutic option for end-stage liver disease.
Yang WS, Choe MS, Lo C
… +21 more, Liu HW, Cho YM, Kim J, Kiral FR, Scandura M, Lu X, Kim KY, Na K, Qiu C, Wu F, Dirks A, Mathew R, Cakir B, Cha HJ, Kim SF, Cox A, Chung S, Jiang YH, Shin K, Lee SH, Park IH
Cell Stem Cell
· 2026 Jul · PMID 42184826
·
Full text
Human emotional and stress responses are orchestrated by subcortical limbic circuits, with the amygdala playing a central role in integrating affective, sensory, and endocrine signals. Despite the urgent need to understa...Human emotional and stress responses are orchestrated by subcortical limbic circuits, with the amygdala playing a central role in integrating affective, sensory, and endocrine signals. Despite the urgent need to understand how these circuits develop and contribute to anxiety and stress-related disorders, progress has been hindered by lack of ex vivo human models. Here, we generated human amygdala-like telencephalic organoids (hATOs) that recapitulate cellular composition, region-specific development, and key features of the amygdala. By assembling hATOs with a hypothalamic organoid (hypoTO) with paraventricular nucleus (PVN)-like features, we modeled the amygdala-hypothalamus-like interaction, which enabled circuit-level analysis of stress-responsive signaling. Exposure to cortisol led to robust upregulation of BCYRN1, a primate-specific retrotransposon-derived noncoding RNA, which uncovered a previously unrecognized mechanism of stress hormone signaling to retrotransposon biology and human-specific synaptic regulation. These findings highlight the potential of hATOs to understand molecular features of affective circuitry underlying emotion and the stress response and neuropsychiatric disorders.
Functional restoration of vision in adult mammals remains unattainable following complete transection of the optic nerve. In this study, we address this challenge by heterotopically transplanting human retinal organoids...Functional restoration of vision in adult mammals remains unattainable following complete transection of the optic nerve. In this study, we address this challenge by heterotopically transplanting human retinal organoids into the transection cavity of the optic nerve in adult rats. One month after transplantation, treated animals exhibited partial recovery of visual function, including a direct pupillary light reflex, visually evoked electrophysiological responses, and visually guided behaviors, which were sustained for at least 3 months. Neuroanatomical tracing and three-dimensional imaging revealed the formation of a structured host-graft coupling spanning the transection gap. Functional engagement of the graft was further supported by chemogenetic inhibition, which led to coordinated attenuation of visual function. Together, these findings provide proof of concept that heterotopic retinal organoid transplantation can establish a relay-like pathway supporting partial functional signal transmission across a completely transected optic nerve, offering an alternative conceptual framework for repairing severe optic nerve injuries.
Zhang Z, Carlisle AK, Carter HP
… +18 more, Lowe JR, Mutlu-Smith M, Lee W, Leiter O, Zhang S, Harding A, Syed M, Brici D, Overall RW, Rund N, Steinhauer C, Blackmore DG, Ayton S, Bush AI, Chen M, Kempermann G, Hou ST, Walker TL
Adult hippocampal neurogenesis declines with age, but the stress pathways that shape neural precursor cell (NPC) survival and lineage progression remain incompletely understood. Here, we tested whether ferroptosis-relate...Adult hippocampal neurogenesis declines with age, but the stress pathways that shape neural precursor cell (NPC) survival and lineage progression remain incompletely understood. Here, we tested whether ferroptosis-related vulnerability contributes to the regulation of hippocampal NPCs and their progeny. Using in vitro assays, transcriptomic analyses, and in vivo genetic and pharmacologic perturbations, we find that NPCs show features consistent with elevated susceptibility to ferroptotic stress relative to more differentiated hippocampal populations. Reducing glutathione peroxidase 4 (GPX4) or increasing ferroptotic stress impairs neurogenesis-associated cellular and behavioral phenotypes, whereas pathway modulation improves selected outcomes in aged animals. These effects were context dependent, with distinct consequences across age and behavioral paradigms. Together, the findings support a model in which ferroptosis-related susceptibility contributes to the regulation of adult hippocampal neurogenesis and cognition.
Cell Stem Cell
· 2026 Jun · PMID 42167216
·
Full text
Despite decades of research, mesenchymal stem/stromal cell (MSC) therapy development has fallen short of expectations. Although regulatory convention prioritizes viability-centric metrics as proxies for potency, emerging...Despite decades of research, mesenchymal stem/stromal cell (MSC) therapy development has fallen short of expectations. Although regulatory convention prioritizes viability-centric metrics as proxies for potency, emerging evidence indicates that, in specific inflammatory contexts, efficacy is driven by apoptotic MSCs undergoing host efferocytosis. This paradox calls into question key assumptions underlying the "living-drug" paradigm. Here, I propose a "precision product" framework to resolve this dichotomy. By integrating conflicting data on cryopreservation, apoptosis, and metabolic activity, I discuss how paracrine signaling and apoptosis represent different phases of a functional continuum. Efficacy is not intrinsic to viability alone but depends on matching the product's state (secretory versus apoptotic) to the host's specific disease microenvironment. Ultimately, by abandoning reductionist "one-size-fits-all" manufacturing in favor of a precision product framework that embraces product heterogeneity and matches specific mechanisms of action to distinct disease microenvironments, the field can overcome current translational bottlenecks and more fully realize the therapeutic potential of MSC therapies.
Zhang T, Fan L, Yao F
… +24 more, Li G, Lin G, Yang Y, Qian F, Liu C, Tang Q, Wang W, Xu C, Xu X, Chang Y, Yang W, Gong J, Wang Y, Huang S, Guan R, Lin L, Jing Q, Yang Z, Pan T, Cheng X, Song L, Du M, Luo Z, Zeng A
Heart rhythm and contraction are initiated by electrical impulses generated by the sinoatrial node (SAN) and modulated by intrinsic cardiac neural inputs. Despite its physiological importance, human in vitro systems that...Heart rhythm and contraction are initiated by electrical impulses generated by the sinoatrial node (SAN) and modulated by intrinsic cardiac neural inputs. Despite its physiological importance, human in vitro systems that recapitulate neural-SAN interactions are lacking. Here, we develop SAN-plexus assembloids by integrating human pluripotent stem cell-derived SAN organoids (SANOs) with cardiac ganglionated plexus organoids (CGPOs), together with atrial-like cardiac organoids, to model pacemaker-to-atrial conduction in a tri-assembloid system. This platform exhibits molecular, structural, and electrophysiological features of human pacemaker activity and enables functional interrogation of neural control over SAN automaticity, including disease-associated conduction dysfunction. By integrating spatial transcriptomics of human SAN tissue with assembloid-based functional analyses, we identify a neuron-to-pacemaker signaling program in which CGPO-derived prosaposin engages the SAN-enriched receptor GPR37 to promote pacemaker maturation. Together, this work establishes SAN-plexus assembloids as a human platform for studying intrinsic neuro-cardiac interactions in pacemaker development and disease.
Lei L, Kaufmann MM, Lao J
… +20 more, Thoulass G, Ammann S, Xiao H, Rhiel M, Dettmer-Monaco V, Grünewald J, Andrieux G, Alzubi J, Miller BR, Weißert K, Gräßel L, Schell C, Illert AL, Joung JK, Boerries M, Cornu TI, Ehl S, Erlacher M, Aichele P, Cathomen T
Cell Stem Cell
· 2026 Jun · PMID 42134322
·
Full text
Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. Here, we applied cytosine base...Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62%-89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type-specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR-Cas9. Although off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish base editing as a therapeutic strategy for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide the clinical translation of genome editors.
Hepatic ketogenesis generates ketone bodies as an alternative energy source during carbohydrate restriction or ketogenic diets, yet its role in non-hepatic cell types remains poorly defined. Here, we show that leukemic s...Hepatic ketogenesis generates ketone bodies as an alternative energy source during carbohydrate restriction or ketogenic diets, yet its role in non-hepatic cell types remains poorly defined. Here, we show that leukemic stem cells (LSCs) in acute myeloid leukemia (AML) exhibit elevated ketogenesis, driven by fatty acid oxidation (FAO), to produce β-hydroxybutyrate (BHB). LSCs express high levels of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 2 (HMGCS2), the rate-limiting enzyme in ketogenesis, compared with blast cells and normal hematopoietic stem cells (HSCs). Deletion of Hmgcs2 in AML cells markedly decreases BHB levels, disrupts LSC function, and impairs leukemia progression in both mouse and human AML models while largely sparing normal hematopoiesis. Mechanistically, BHB suppresses ferroptosis by limiting pro-ferroptotic phospholipid remodeling through epigenetic regulation of fatty acid desaturase 2 (FADS2). Together, these findings identify autonomous ketogenesis as a critical metabolic program that protects LSCs from ferroptotic cell death and sustains leukemia progression.
The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling o...The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5 monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.
Hepatocyte-based therapies represent a promising alternative to liver transplantation, yet their clinical translation is constrained by the limited availability of functional cells and inefficient engraftment. Here, we r...Hepatocyte-based therapies represent a promising alternative to liver transplantation, yet their clinical translation is constrained by the limited availability of functional cells and inefficient engraftment. Here, we review progress in the field from a translational perspective, focusing on strategies to overcome these core challenges. We analyze emerging cell sources derived from stem cell technologies and assess their therapeutic potential. These translational efforts are organized around two clinical paradigms: hepatocyte replacement for long-term functional correction and temporary hepatocyte support for liver failure. Beyond hepatocytes, we also discuss preclinical and translational advances involving other liver cell types. To conclude, we outline critical gaps that need to be addressed for clinical translation, including scalable good manufacturing practice (GMP)-compliant manufacturing, efficient preconditioning regimens, long-term immune compatibility with non-invasive graft monitoring, and patient stratification for optimal clinical outcomes. We also discuss how hepatocyte-based therapies can complement gene/RNA therapies and xenotransplantation to broaden treatment options for liver diseases.
In a recent study in Science, Chen et al. engineer astrocytes with anti-amyloid chimeric antigen receptors (CARs) to enable sustained, antigen-directed clearance of amyloid-β (Aβ) in vivo, revealing how CAR design can sh...In a recent study in Science, Chen et al. engineer astrocytes with anti-amyloid chimeric antigen receptors (CARs) to enable sustained, antigen-directed clearance of amyloid-β (Aβ) in vivo, revealing how CAR design can shape both pathology and glial responses.
Niu et al. introduce SPTEdU-seq, a strategy that integrates spatial transcriptomics with EdU-based temporal labeling to jointly capture transcriptional states and proliferative history. This approach provides a framework...Niu et al. introduce SPTEdU-seq, a strategy that integrates spatial transcriptomics with EdU-based temporal labeling to jointly capture transcriptional states and proliferative history. This approach provides a framework for resolving spatiotemporal cell dynamics in development, regeneration, and cancer.
Menstruation entails repeated cycles of cyclical shedding and scarless regeneration of the endometrium, yet the precise cellular states underlying this process have remained poorly defined. In this issue, Nikolakopoulou...Menstruation entails repeated cycles of cyclical shedding and scarless regeneration of the endometrium, yet the precise cellular states underlying this process have remained poorly defined. In this issue, Nikolakopoulou et al. establish an in vitro menstrual cycle (IVMC) protocol using human endometrial organoids, revealing WNT7A as a central regulator of epithelial regeneration.
Kunitomi H, Khaine AM, Jamee R
… +12 more, Arreola V, Lancero M, Raychaudhuri A, Perli S, Sato Y, Iwasaki M, Ruivo P, Tomoda K, Mito M, Shichino Y, Iwasaki S, Yamanaka S
eIF4G2 (DAP5/NAT1) is a non-canonical translation initiation factor, but its role in homeostasis is unclear. Using inducible Eif4g2 knockout mice and intestinal organoids, we show that eIF4G2 loss collapses Lgr5 intestin...eIF4G2 (DAP5/NAT1) is a non-canonical translation initiation factor, but its role in homeostasis is unclear. Using inducible Eif4g2 knockout mice and intestinal organoids, we show that eIF4G2 loss collapses Lgr5 intestinal stem cell (ISC) and secretory maturation programs while preserving villus architecture. Transcriptomic and single-nucleus multiome analyses reveal a durable fetal-like/regenerative state with YAP-TEAD activation and regenerative absorptive cells. Ribosome profiling identifies selective translation-efficiency loss among chromatin regulators, especially the KAT3 coactivators CREBBP and EP300, resulting in reduced KAT3 abundance and global histone acetylation; chemical KAT3 inhibition phenocopies this state. CUT&Tag and assay for transposase-accessible chromatin sequencing (ATAC-seq) demonstrate that reduced eIF4G2-KAT3 output drives locus-selective enhancer remodeling, with loss of adult ISC/Wnt-Notch elements and activation of TEAD-enriched fetal loci, without inflammatory or integrated stress response programs driving the transition. Fetal intestinal spheroids remain viable despite similar biochemical defects, highlighting a stage-specific requirement for translational buffering in maintaining adult identity.
Menstruation is an unusual process in which the human endometrium undergoes cyclical shedding with scarless regeneration. Despite its pivotal role in reproductive health, the cellular states and interactions orchestratin...Menstruation is an unusual process in which the human endometrium undergoes cyclical shedding with scarless regeneration. Despite its pivotal role in reproductive health, the cellular states and interactions orchestrating this process remain poorly defined, largely due to the lack of in vitro systems that capture the inaccessible perimenstrual window. We use human endometrial organoids to establish an in vitro menstrual cycle (IVMC) protocol that recapitulates cyclical epithelial dynamics. We validate the IVMC by benchmarking against in vivo samples spanning the menstrual window through histology, transcriptomic, and multiplex secreted-protein analysis. During menstruation, the in vivo luminal epithelium acquires a distinct transcriptomic signature, characterized by WNT7A expression. Loss of WNT7A compromises long-term organoid survival, highlighting its functional importance. The regeneration-associated luminal epithelium acts as a signaling hub during regeneration through interactions with the vasculature. This work opens new avenues to dissect the unique regenerative program of the endometrium in health and disease.