Kiral FR, Yang WS, Iyilikci O
… +8 more, Lu X, Kim J, Choe MS, Lo C, Zhong M, Kim KY, Jiang YH, Park IH
Cell Stem Cell
· 2026 Jan · PMID 41475351
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The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem ce...The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem cells, modeling pineal development and function. Single-cell RNA sequencing revealed distinct mature and developing pinealocyte populations with transcriptomic profiles closely resembling the in vivo pineal gland. hPGOs produce melatonin, express adrenergic receptors, and respond to noradrenaline, mimicking physiological regulation. To model disease-related impairments, we generated hPGOs from Angelman syndrome (AS) patient-derived iPSCs, which exhibit disrupted pinealocyte differentiation and markedly reduced melatonin synthesis, reflecting AS-related developmental pathology. Additionally, transplanted hPGOs restored circulating melatonin in pinealectomized mice, demonstrating their potential for cell-therapy approaches. These findings establish hPGOs as a robust platform for probing pineal development, circadian regulation, and their disruption in neurodevelopmental and sleep-related disorders.
Endo R, Sugimoto S, Kuwashima Y
… +12 more, Matano M, Hanyu H, Takahashi S, Kato H, Tanaka T, Sihombing AM, Shirosaki K, Hatano Y, Sugiura Y, Kanai T, Wada M, Sato T
Short bowel syndrome (SBS) is a life-threatening condition in which outcomes often critically depend on ileal function, the only intestinal segment specialized for bile acid uptake and efficient fat absorption. However,...Short bowel syndrome (SBS) is a life-threatening condition in which outcomes often critically depend on ileal function, the only intestinal segment specialized for bile acid uptake and efficient fat absorption. However, whether restoring ileal epithelium-specific nutrient absorption can ameliorate SBS has remained unknown. Here, we demonstrate a niche-preserving transplantation strategy enabling highly efficient engraftment of intestinal organoids into the rat small intestine. Clearing luminal mucus with N-acetylcysteine facilitates ethylenediaminetetraacetic acid (EDTA)-based epithelial detachment, enabling removal of Lgr5 stem cells while preserving the stromal niche. This preconditioning increased the engrafted area and enabled the generation of an ilealized jejunum that improved body-weight trajectories and survival in rat SBS. Furthermore, the engrafted epithelia endowed the jejunum with bile acid absorption capacity. These findings provide in vivo evidence for stem cell niche theory, showing that the niche is essential to accommodate donor stem cells, and establish ilealized jejunum as a path toward autologous, region-targeted therapy for SBS.
Zhang Y, Tan C, Liu Z
… +20 more, Mao X, Jiang C, Mohammed AN, Li X, Lu R, Wang A, Maihemuti W, Pek N, Fu H, Milbes O, Pandrangi K, Johnson CP, Sekar V, Liu Y, Lai L, Pryhuber GS, Kalinichenko VV, Miao Y, Guo M, Gu M
Cell Stem Cell
· 2026 Jan · PMID 41448181
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Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity with no curative therapy, characterized by impaired alveologenesis and capillary formation. However, the molecular mechanisms underlying endotheli...Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity with no curative therapy, characterized by impaired alveologenesis and capillary formation. However, the molecular mechanisms underlying endothelial dysfunction, a key driver of BPD pathogenesis, remain poorly understood. Through multiomic profiling of endothelial cells isolated from human BPD lungs, we identified an expansion of general capillary endothelial cells (gCaps) marked by neurotrophic receptor tyrosine kinase 2 (NTRK2). Notably, we uncovered a critical isoform switch that governs gCap regeneration. Full-length NTRK2 (NTRK2-FL) promoted gCap repair after hyperoxic injury, whereas RBFOX2-mediated splicing of NTRK2-FL into a truncated isoform (NTRK2-T1) contributed to maladaptive responses and persistent alveolar simplification. Restoring NTRK2-FL using lipid nanoparticle-delivered mRNA promoted angiogenesis in vessel organoids and reversed alveolar simplification in hyperoxic mice. These findings identified NTRK2 isoform imbalance as a key driver of endothelial dysfunction and support isoform-specific RNA therapy as a promising strategy for vascular regeneration and repair.
Song J, Zhao R, Zhang Y
… +24 more, Lu M, Liu P, Li T, Li C, Yu R, Chen X, Yang H, Zhang X, Su Y, Han Y, Sun D, Zhou Q, Hou Z, Liu W, Gao X, Tao W, Zhang J, Wang J, Qin Y, Wang H, Wu K, Wu J, Chen ZJ, Zhao H
Embryo-maternal interaction is essential for post-implantation human development. While endometrial organoids have enabled in vitro modeling of the uterine environment, a fully integrated 3D co-culture system with human...Embryo-maternal interaction is essential for post-implantation human development. While endometrial organoids have enabled in vitro modeling of the uterine environment, a fully integrated 3D co-culture system with human embryos has not been established. Here, we develop a physiologically relevant 3D platform that supports the co-culture of human embryos with endometrial organoids, enabling reciprocal embryo-maternal communication. This system sustains development to day 14 post-fertilization with structural and molecular fidelity to Carnegie stage landmarks, including yolk sac formation, primordial germ cell specification, and trophoblast maturation. Single-cell transcriptomics and functional assays reveal that the endometrial niche accelerates extravillous trophoblast emergence at day 9 post-fertilization and primes their invasive programs. Disruption of maternal signals, including human chorionic gonadotropin signaling blockade, markedly impairs embryonic progression. This co-culture system provides a powerful and tractable model to dissect human peri- and post-implantation development, with broad relevance to early pregnancy loss, placental biology, and reproductive medicine.
Severe respiratory viral infections lead to extensive damage to the alveolar epithelium and also induce a robust immune response. How the immune microenvironment interacts with lung stem/progenitor cells and impacts alve...Severe respiratory viral infections lead to extensive damage to the alveolar epithelium and also induce a robust immune response. How the immune microenvironment interacts with lung stem/progenitor cells and impacts alveolar regeneration is poorly understood. Here, we found that dysplastic KRT5 basal-like cells, which emerge after severe viral infections, contribute to the recruitment and sequestration of CD4 effector and CD8 T cells in the lung after viral clearance in a CXCR3- and integrin α4β7-dependent manner. Persistent CD4 effector and CD8 T cells impair alveolar regeneration mediated via airway secretory cells by secreting IFNγ, thereby inhibiting lung functional repair. Importantly, anti-IFNγ treatment improves alveolar regeneration and lung function in vivo. Overall, our study reveals the pathogenetic role of dysplastic KRT5 cells in alveolar regeneration, serving as a niche for tissue-resident lymphocytes that specifically inhibit alveolar regeneration. Additionally, our findings provide a potential therapeutic strategy to improve alveolar regeneration after viral pneumonia.
Glass MR, Matoba N, Beltran AA
… +36 more, Patel NK, Farah TM, Eswar K, Bhargava S, Huang K, Curtin I, Ahmed S, Srivastava M, Drake E, Davis LT, Yeturi M, Sun K, Love MI, Simon JM, John TS, Marrus N, Pandey J, Estes A, Dager S, Schultz RT, Botteron K, Evans A, Kim SH, Styner M, McKinstry RC, Collins DL, Volk H, Benke K, Zwaigenbaum L, Hazlett H, Beltran AS, Girault JB, Shen MD, Piven J, Stein JL, Infant Brain Imaging Study Network
Cell Stem Cell
· 2026 Jan · PMID 41435817
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Induced pluripotent stem cell (iPSC)-derived human cortical organoids (hCOs) model neurogenesis on an individual's genetic background. The degree to which hCO phenotypes recapitulate the brain growth of the participants...Induced pluripotent stem cell (iPSC)-derived human cortical organoids (hCOs) model neurogenesis on an individual's genetic background. The degree to which hCO phenotypes recapitulate the brain growth of the participants from whom they were derived is not well established. We generated up to 3 iPSC clones from each of 18 participants in the Infant Brain Imaging Study, who underwent longitudinal brain imaging during infancy. We identified consistent hCO morphology and cortical cell types across clones from the same participant. hCO cross-sectional area and production of hem/choroid plexus were associated with in vivo cortical growth rates. Cell-cycle-associated gene expression in early progenitors at the crux of fate-decision trajectories was correlated with cortical growth rates from 6 to 12 months of age and was enriched for microcephaly and neurodevelopmental disorder genes. Our data suggest the hCOs capture inter-individual variation in cortical cell types that influences infant cortical surface area expansion.
The sympathetic ganglia are essential components of the nervous system that regulate various aspects of involuntary body functions. Recapitulating sympathetic ganglion development with three-dimensional (3D) organoids is...The sympathetic ganglia are essential components of the nervous system that regulate various aspects of involuntary body functions. Recapitulating sympathetic ganglion development with three-dimensional (3D) organoids is challenging and has not been achieved. Here, we report a method to differentiate human pluripotent stem cells into 3D neural organoids that resemble peripheral sympathetic ganglia, producing both neurons and glial cells of the ganglia in a self-organized manner. We developed an organoid system to construct functional connections between the sympathetic ganglia and one of their peripheral targets, the heart, by fusing human sympathetic ganglion organoids (hSGOs) and heart-forming organoids. Notably, this system enables the evaluation of signaling controls (i.e., nerve growth factor [NGF] signaling) on human sympathetic-to-cardiac innervation and reveals the reciprocal impacts between the sympathetic and cardiac lineages during their co-development. Our study provides a physiologically relevant platform for understanding the development of human sympathetic ganglia, their crosstalk with peripheral targets, and related diseases.
Microglia are indispensable for the central nervous system (CNS) development and homeostasis, and mutations in microglia can cause microgliopathies. Correcting these mutations holds therapeutic potential, but conventiona...Microglia are indispensable for the central nervous system (CNS) development and homeostasis, and mutations in microglia can cause microgliopathies. Correcting these mutations holds therapeutic potential, but conventional gene therapies cannot yet achieve the CNS-wide delivery required for meaningful treatment. Microglia replacement has emerged as a groundbreaking paradigm that removes pathogenic microglia and introduces healthy donor cells. Over the past 5 years (2020-2025), the field has advanced rapidly from first achieving efficient replacement in animals to first-in-human clinical interventions. Here, we summarize microgliopathies as therapeutic targets and trace the historical and technical evolution from the pre-replacement era of low-engraftment approaches to efficient strategies enabling widespread replacement. We outline the mechanistic principles and current methods that underpin efficient replacement. We highlight therapeutic applications ranging from gene correction to engineered "Trojan horse" microglia and explore potential ability enhancement. Finally, we discuss the potential risks and future directions for safe, scalable, and ethically governed clinical translation.
Through a comprehensive analysis of stem cell clinical research in China, we reveal robust yet uneven translational linkages between IITs and INDs and propose governance reforms to reduce redundancy, enhance efficiency,...Through a comprehensive analysis of stem cell clinical research in China, we reveal robust yet uneven translational linkages between IITs and INDs and propose governance reforms to reduce redundancy, enhance efficiency, and better align exploratory research with regulatory and industrial pathways.
Recent advances in human embryo culture and revised guidelines from the International Society for Stem Cell Research (ISSCR) give grounds for extending the 14-day limit. To prepare for any possible future change in China...Recent advances in human embryo culture and revised guidelines from the International Society for Stem Cell Research (ISSCR) give grounds for extending the 14-day limit. To prepare for any possible future change in China's regulation, we propose a path toward cautious extension with strict oversight, balancing scientific progress with ethical responsibility.
In this issue of Cell Stem Cell, Wang et al. generate human nucleus basalis of Meynert organoids (hnbMOs), establish a human-specific cholinergic projection system in transplanted assembloids, and identify projection def...In this issue of Cell Stem Cell, Wang et al. generate human nucleus basalis of Meynert organoids (hnbMOs), establish a human-specific cholinergic projection system in transplanted assembloids, and identify projection deficits in Down syndrome-derived assembloids. This study provides a valuable model for investigating nbM-related neural circuits and neurological disorders.
Adult mammalian hearts exhibit limited regenerative capacity. Fan et al. report that neonatal cardiomyocyte-derived clusterin competes for macrophage Toll-like receptor 4 to suppress inflammation and induces reparative p...Adult mammalian hearts exhibit limited regenerative capacity. Fan et al. report that neonatal cardiomyocyte-derived clusterin competes for macrophage Toll-like receptor 4 to suppress inflammation and induces reparative polarization. This cardio-immune dialogue activates BMP2 signaling to stimulate cardiomyocyte proliferation, reframing inflammation as a cooperative driver of heart repair.
Pham J, Nandi SP, Balaian L
… +17 more, Engstrom C, Chang P, Mack K, van der Werf I, Klacking E, Sneifer J, Katragadda N, Wirtjes K, Ruiz A, Chilin-Fuentes D, Molina E, Mesci P, Stoudemire J, Morris SR, Whisenant T, Alexandrov LB, Jamieson CHM
Cell Stem Cell
· 2025 Dec · PMID 41289992
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Previous reports revealed immune dysfunction, chromosomal abnormalities, cytokine deregulation, and telomere alterations after prolonged spaceflight. However, the stress of space on hematopoietic stem and progenitor cell...Previous reports revealed immune dysfunction, chromosomal abnormalities, cytokine deregulation, and telomere alterations after prolonged spaceflight. However, the stress of space on hematopoietic stem and progenitor cells (HSPCs) and the resilience properties maintaining lifelong hematopoiesis and immunity were not studied. We performed HSPC functionally organized multi-omics aging and resilience (HSPC-FOMA-R) analyses in 9 astronauts before, during, and after three short-duration International Space Station (ISS) missions. Whole-genome sequencing (with telomere length analysis and mitochondrial and clonal mutational profiling), whole-transcriptome sequencing (with RNA editing and retrotransposon analyses), single-cell RNA sequencing, cytokine arrays, and fluorescence-activated cell sorting (FACS) analyses assessed HSPC and immune subpopulation survival dynamics. We show that spaceflight is associated with partially reversible changes in HSPC survival and self-renewal, adenosine deaminase associated with RNA1 (ADAR1), telomere maintenance, mobilization, cell cycle, and "fight or flight" gene expression. Combined with clonal hematopoietic mutations, apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3C) activation, and retrotransposon deregulation, HSPC-FOMA-R analyses are needed before extended missions.
Arif T, Qiu J, Khademian H
… +12 more, Lohithakshan A, Menon A, Menon V, Slavinsky M, Batignes M, Lin M, Sebra R, Beaumont KG, Benson DL, Tzavaras N, Ménager MM, Ghaffari S
Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging-beyond their passive mediation of autophagy-is unclear. We show th...Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging-beyond their passive mediation of autophagy-is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.
Li Q, Nikolova MT, Zhang G
… +10 more, Cervenka I, Valigi F, Burri D, Plantier E, Mazzoleni A, Lamouline A, Schwaller J, Treutlein B, Martin I, García-García A
Endosteal bone marrow (BM) niches are crucial to sustain non-steady-state hematopoiesis but are challenging to be modeled in their cellular and molecular complexity in standardized, human settings. We report a developmen...Endosteal bone marrow (BM) niches are crucial to sustain non-steady-state hematopoiesis but are challenging to be modeled in their cellular and molecular complexity in standardized, human settings. We report a developmentally guided approach to generate a macro-scale organotypic model of BM endosteal niches (engineered vascularized osteoblastic niche [eVON]) based on human induced pluripotent stem cells and porous hydroxyapatite scaffolds. The eVON contains long-lasting vascular networks covered by pericytes and neural fibers within an osteogenic matrix. Key niche signals (CXCL12, KITLG, and vascular endothelial growth factor A [VEGFA]) are expressed in human-specific patterns. The system supports hematopoiesis in vitro and preserves hematopoietic stem and progenitor cell (HSPC) multilineage repopulation capacity in vivo. eVON perturbations at cellular (removing vasculature) and molecular (deregulating VEGF-A and CXCL12 signaling) levels enabled the investigation of the contribution of endosteal vasculature to myelopoiesis. The eVON faithfully captures phenotypic, structural, and functional features of human endosteal BM, enabling the study of pathophysiological interactions with hematopoietic cells.
Fan L, Tang Q, Wang Y
… +15 more, Sun H, Li G, Yang Y, Zhu H, Liu Z, Wang H, Wang H, Jing Q, Antos CL, Xiao H, Guan R, Pei G, Ginhoux F, Zhou Z, Zeng A
Adult hearts scar after injury, while neonatal hearts regenerate. The mechanisms underlying this dichotomy remain unclear. Through comparative spatiotemporal single-cell analyses and dual recombinase-mediated lineage tra...Adult hearts scar after injury, while neonatal hearts regenerate. The mechanisms underlying this dichotomy remain unclear. Through comparative spatiotemporal single-cell analyses and dual recombinase-mediated lineage tracing, we uncovered an injury-induced Clusterin cardiomyocyte (Clu CM) population that coordinates reparative, anti-inflammatory macrophage activity. Following injury, Clu CMs emerge in the border zone of regenerative hearts but are scarce in non-regenerative contexts. These CMs secrete CLU, which binds to macrophage Toll-like receptor 4 (TLR4), attenuating inflammation and promoting reparative polarization through Cpt1a-dependent fatty acid oxidation. These macrophages secrete bone morphogenetic protein 2 (BMP2), activating bone morphogenetic protein receptor, type 1A (BMPR1A) signaling in CMs to drive proliferation. Reduced CLU levels in myocardial infarction patients correlate with impaired cardiac function, whereas Clu overexpression or transplantation of engineered CLU human cardiac organoids recapitulates this regenerative modulation, enhancing myocardial repair in adult mice. Our findings reveal a critical cardio-immune mechanism whereby Clu CMs reprogram macrophages to resolve inflammation and stimulate CM proliferation, providing potential strategies for cardiac regeneration.
Tissues are constantly exposed to stresses that cause both cellular and structural damage. In response, a coordinated healing process restores tissue integrity and functionality. When these stresses persist or the healin...Tissues are constantly exposed to stresses that cause both cellular and structural damage. In response, a coordinated healing process restores tissue integrity and functionality. When these stresses persist or the healing process becomes dysregulated, progressive tissue fibrosis can emerge. This condition is characterized by excessive scarring, disrupted tissue architecture, and loss of organ function. In this review, we explore the relationship between regeneration and fibrosis, with a focus on the lung and liver. We dissect cellular contributions and interplay among fibroblasts, epithelial progenitors, immune components, and vasculature in both regenerative and fibrotic responses to tissue injury. We also examine therapeutic strategies under development that navigate the complexities of immune mediators, fibrogenic myofibroblasts, and excess extracellular matrix (ECM) with small-molecule targeting and various cell-based approaches. By elucidating regulatory networks controlling regeneration and fibrosis, we aim to inform the development of targeted strategies to alleviate or reverse fibrosis, ultimately supporting long-term tissue health.
The number of retinal pigment epithelium (RPE) transplantation clinical trials for dry age-related macular degeneration (AMD) is increasing quickly, with groups using different stem cell sources, delivery approaches, and...The number of retinal pigment epithelium (RPE) transplantation clinical trials for dry age-related macular degeneration (AMD) is increasing quickly, with groups using different stem cell sources, delivery approaches, and immune suppression. We discuss the recent success in a phase 1/2a clinical trial evaluating allogeneic RPE stem cell-derived RPE cells isolated from the RPE layer of human cadaveric eyes.
Low yields of dopamine neurons in human stem cell-derived neural grafts limit their potential for treating Parkinson's disease. Zhang et al. develop a new three-dimensional differentiation method, informed and refined th...Low yields of dopamine neurons in human stem cell-derived neural grafts limit their potential for treating Parkinson's disease. Zhang et al. develop a new three-dimensional differentiation method, informed and refined through careful clonal linage tracing of donor cells post-transplantation, to improve dopamine neuron purity of grafts, eliminating unwanted, off-target populations.
Lee JY, Reyes N, Woo SH
… +12 more, Allen NC, Kadota T, Lechner A, Biswas R, Goel S, Stratton F, Kuang C, Tsukui T, Auyeung V, Mansfield AS, LaFave LM, Peng T
Cell Stem Cell
· 2025 Dec · PMID 41187746
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Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify...Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears p16+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.