Wu Z, Zou X, Chen C
… +18 more, Zhou M, Yue X, Guo D, Gao Y, Ma C, Han Q, Yang D, Zang D, Song R, Li Y, Pang S, Ren H, Zhang W, Zhang M, Zhang Y, Yang J, Jiang X, Zhang C
Overwhelming cardiomyocyte death and excessive cardiac fibrosis post myocardial infarction (MI) collectively lead to heart failure and mortality. For treating this devastating disease, it is essential to eliminate fibros...Overwhelming cardiomyocyte death and excessive cardiac fibrosis post myocardial infarction (MI) collectively lead to heart failure and mortality. For treating this devastating disease, it is essential to eliminate fibrosis and reconstitute the damaged myocardium, yet effective strategies remain elusive. Here, we created pleiotropic chimeric antigen receptor-monocytes (pCAR-Mos), revitalizing the injured heart via synergistic fibrosis clearance and myocardial reconstitution. Specifically, we engineered monocytes to express fibroblast activation protein (FAP)-chimeric antigen receptor (CAR) and secrete the cardioregenerative protein Agrin. CAR-mediated phagocytosis of myofibroblasts, which was further enhanced by Agrin, significantly attenuated fibrotic scar formation. Moreover, Agrin secretion promoted cardiomyocyte regeneration, thereby facilitating replenishment of functional myocardium. Treatment with pCAR-Mos remodeled the cardiac fibrotic microenvironment and substantially restored cardiac function in MI mice. In sum, our findings confirmed that pCAR-Mos exerted potent phagocytic activity against profibrotic myofibroblasts while simultaneously enabling myocardial reconstitution, thereby providing a reversible treatment strategy for MI with broad application in other fibrotic diseases.
Tosoni G, Ayyildiz D, Snoeck S
… +22 more, Moreno-Jiménez EP, Penning A, Santiago-Mujika E, Ruiz Ormaechea O, Lee H, Poovathingal S, Davie K, Bryois J, Macnair W, Anink J, De Vries LE, Farmand S, Nutma E, Swaab DF, Aronica E, Middeldorp J, Thuret S, Roybon L, Basak O, Fitzsimons CP, Lucassen PJ, Salta E
The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain an open question. Although rodent studies have highlighted active...The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain an open question. Although rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus both under healthy conditions and in Alzheimer's disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD, and dementia-resilient human hippocampus samples to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. By applying an integrated experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles reflecting "juvenile" cellular functions, which are compromised in AD. Our findings suggest that the presence of these immature neuronal populations per se may actively contribute to maintaining homeostasis within the aged human hippocampus and to cognitive resilience in AD.
Kafkia E, Pladevall-Morera D, Argemi-Muntadas L
… +11 more, Wang G, Noberini R, Casòliba-Melich A, Bagés-Arnal S, Anagho-Mattanovich M, Silvério-Alves R, Gassler J, Bonaldi T, Rabelink TJ, Moritz T, Żylicz JJ
Cell Stem Cell
· 2026 May · PMID 42034059
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Full text
Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metab...Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.
Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) relapse and therapy resistance, predominantly through immune evasion. Here, we identify multimerin 1 (MMRN1) as being highly and specifically expressed in LSC...Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) relapse and therapy resistance, predominantly through immune evasion. Here, we identify multimerin 1 (MMRN1) as being highly and specifically expressed in LSCs. Mechanistically, MMRN1 activates the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 1 (STAT1) pathway via its epidermal growth factor (EGF)-like domain, suppressing Neu5Ac degradation to drive sialylglycan accumulation, which forms glycoimmune checkpoints functionally akin to programmed death 1 (PD-1)/the cytotoxic T-lymphocyte antigen-4 (CTLA-4). These sialylglycans activate the sialylglycan-Siglec immune checkpoint axis, impairing T/natural killer (NK) cell activity and enabling LSC immune evasion. Additionally, MMRN1 sustains LSC self-renewal via the EGFR/STAT5/CD9 pathway. Genetic ablation of MMRN1 markedly suppresses AML progression and synergizes with anti-PD-L1/CTLA-4 therapy. In a clinical trial (ChiCTR2500097714), erlotinib (an EGFR inhibitor) combined with azacitidine plus the HAG regimen, which consists of homoharringtonine, a low dose of cytarabine, and granulocyte colony-stimulating factor priming, achieves a remission rate of 75% in relapsed/refractory AML, likely via MMRN1/EGFR axis blockade. Our findings establish MMRN1 as a dual-functional target for LSC maintenance and immune evasion and propose that disrupting MMRN1 or EGFR remodels the immunosuppressive tumor microenvironment, offering a promising strategy for AML immunotherapy.
The clinical application of human stem cell-derived islet organoids (SC-islets) is hindered by immaturity and ischemia-induced dysfunction post-transplantation. Hypoxia-driven angiogenesis is a common adaptation, but the...The clinical application of human stem cell-derived islet organoids (SC-islets) is hindered by immaturity and ischemia-induced dysfunction post-transplantation. Hypoxia-driven angiogenesis is a common adaptation, but the metabolic fragility of SC-islet β cells leads to early functional damage and suppressed vascular endothelial growth factor A (VEGFA) expression, thereby delaying vascularization and causing graft loss. The key challenge in SC-islet transplantation is how to prevent hypoxia-induced stress and promote rapid angiogenesis. We found that excessive zinc in SC-islet β cells induces oxidative modification that inhibits AMP-activated protein kinase (AMPK) activity. Chemical inhibition of zinc transportation activates AMPK, enhances functional maturation, improves hypoxia resistance, and increases hypoxia-inducible factor 1α (HIF1A)-independent VEGFA expression to facilitate endothelial cell integration. In diabetic animal models, this approach significantly improved hypoxia resistance, accelerated angiogenesis, and enhanced glycemic control. Our findings demonstrate that chemical inhibition of zinc transportation boosts SC-islet functional competence, offering a potential strategy to advance pre-adaptation to stress in regenerative medicine.
Tumor tissue engineering, integrating organoid, microfluidic, and biofabrication technologies, has opened new avenues for cancer research. Leveraging advanced bioengineering and biomaterials, these 3D models capture tumo...Tumor tissue engineering, integrating organoid, microfluidic, and biofabrication technologies, has opened new avenues for cancer research. Leveraging advanced bioengineering and biomaterials, these 3D models capture tumor architecture, cellular heterogeneity, biomechanics, and biochemical characteristics for disease modeling. Despite recognition that tissue organization influences malignancy and drug resistance, clinically oriented 3D approaches are rare, largely due to tumor microenvironment complexity, cellular plasticity, and interpatient heterogeneity. With a primary emphasis on gastrointestinal malignancies, we outline the capabilities and remaining limitations of organoid-based cancer models, including developmentally defined stem cell-derived systems that enable controlled early-stage modeling when premalignant material is scarce. We discuss patient-derived organoids as clinical avatars for therapy response prediction and summarize recent clinical trials that delineate key bottlenecks hindering routine implementation. Finally, we outline how innovations in biomaterial design, biofabrication, and microfluidics, benchmarking against patient data, and artificial intelligence are converging to better reconstruct tumor complexity, improve experimental tractability, and accelerate translation.
Detoxification of endogenous aldehydes is critical for preserving genomic integrity in hematopoietic stem cells. In this issue, Kamimae-Lanning et al. show that excess formaldehyde can drive clonal hematopoiesis through...Detoxification of endogenous aldehydes is critical for preserving genomic integrity in hematopoietic stem cells. In this issue, Kamimae-Lanning et al. show that excess formaldehyde can drive clonal hematopoiesis through attrition of blood-forming progenitors, accelerating neutral drift in the absence of known genetic drivers of positive selection.
Hearing loss has been considered one of the key risk factors for cognitive decline and dementia. Liu et al. establish a causal link between hearing activity, hippocampal neurogenesis, and cognitive function and identify...Hearing loss has been considered one of the key risk factors for cognitive decline and dementia. Liu et al. establish a causal link between hearing activity, hippocampal neurogenesis, and cognitive function and identify the locus coeruleus-norepinephrine system as the mediator.
Autoimmune hepatitis (AIH) is a progressive, life-threatening liver disease that remains treated largely with broad immunosuppression. In this issue of Cell Stem Cell, Jing and colleagues reprogram follicular helper T (T...Autoimmune hepatitis (AIH) is a progressive, life-threatening liver disease that remains treated largely with broad immunosuppression. In this issue of Cell Stem Cell, Jing and colleagues reprogram follicular helper T (Tfh) cells in vivo into antigen-specific FOXP3⁺ CAR-Tfh cells to restore immune tolerance by rewiring core drivers of autoimmunity.
Zinc is required for insulin packaging into secretory granules, yet reduced zinc transporter activity paradoxically enhances beta cell function. In this issue, Wang et al. show that pharmacologic inhibition of zinc trans...Zinc is required for insulin packaging into secretory granules, yet reduced zinc transporter activity paradoxically enhances beta cell function. In this issue, Wang et al. show that pharmacologic inhibition of zinc transport in stem cell-derived islets activates AMPK signaling and improves maturation, hypoxia resistance, VEGFA expression, and graft performance.
Directing the differentiation of human pluripotent stem cells into atrioventricular node-like cells is a critical strategy for restoring atrioventricular node dysfunction in patients. In this issue, Lohbihler et al. defi...Directing the differentiation of human pluripotent stem cells into atrioventricular node-like cells is a critical strategy for restoring atrioventricular node dysfunction in patients. In this issue, Lohbihler et al. define a BMP2-driven protocol to engineer functional conduction bridges that recapitulate the heart's native "gatekeeper" properties in vivo.
Direct induction of cardiomyocytes from fibroblasts represents a promising strategy for cardiac regeneration. However, the transdifferentiation efficiency in vivo remains low. Leveraging a Perturb-seq platform tailored t...Direct induction of cardiomyocytes from fibroblasts represents a promising strategy for cardiac regeneration. However, the transdifferentiation efficiency in vivo remains low. Leveraging a Perturb-seq platform tailored to complex pathological environments, we systematically compared and ranked 140 potential barriers of in vivo cardiac reprogramming. Based on their shRNA distribution and enrichment along the single-cell RNA-seq trajectory, calreticulin (Calr) emerged as a top inhibitor. Calr knockdown greatly enhanced iCM induction efficiency in vitro, enabling synchronized calcium oscillations in iCMs, and accelerated in situ reprogramming after myocardial infarction, improving cardiac function and reducing fibrosis. Mechanistically, Calr knockdown activates calcium signaling, boosting MEF2C activity to drive reprogramming and even substitute for exogenous MEF2C. Collectively, our study reveals critical regulators hindering in situ cardiomyocyte induction in a pathological microenvironment, providing effective reprogramming factors and a strategic framework for cardiac repair and regeneration after myocardial infarction.
Understanding biological processes requires spatiotemporal mapping of proliferative and transcriptional dynamics. Current spatial transcriptomics methods capture only protein-coding transcripts and static snapshots, obsc...Understanding biological processes requires spatiotemporal mapping of proliferative and transcriptional dynamics. Current spatial transcriptomics methods capture only protein-coding transcripts and static snapshots, obscuring non-coding RNAs (ncRNAs) and dynamic events. We developed SPTEdU-seq, integrating spatial total transcriptomics with 5-ethynyl-2'-deoxyuridine tracking to co-profile gene expression and proliferation dynamics. SPTEdU-seq demonstrates ultrahigh sensitivity for coding and non-coding transcripts and for splicing isoforms, with single-molecule probe design eliminating optical imaging. Applied to developing and adult mouse brains, it revealed spatial lncRNA patterns, reconstructed developmental trajectories, and enabled spatiotemporal lineage tracing. In murine ischemic stroke, it mapped regeneration dynamics and identified an Igfbp5 astrocyte subtype within a pro-repair niche. In mouse and human renal tumors, it uncovered tumor-associated splicing and detected diagnostic 3p loss. By profiling newborn and resident cells in intact microenvironments, it unveiled previously inaccessible interaction networks. SPTEdU-seq thus establishes a powerful framework for investigating cell fate dynamics in regeneration, development, and cancer.
The inflammatory pathological microenvironment of osteoarthritis (OA) degrades the cell state and function of stem cell-derived grafts and presents a major obstacle to developing effective cell therapies. Here, we show t...The inflammatory pathological microenvironment of osteoarthritis (OA) degrades the cell state and function of stem cell-derived grafts and presents a major obstacle to developing effective cell therapies. Here, we show that the viability and hyaline cartilage phenotype of bone marrow-derived mesenchymal stem cell (BMSC)-derived chondrocyte microspheroids (CMSs) can be efficiently preserved during spheroidization with persistent H supply and in an OA microenvironment. We therefore developed TiSi nanosheets (TSN) that hydrolytically generate a sustained (> 2 months) high dose of H and construct a H-releasing hydrogel transplant (TSN/CMS-Gel) by encapsulating TSN and CMSs within a photo-crosslinking hydrogel (Gel). Transplantation of TSN/CMS-Gel achieves a strong survival of chondrocytes in a rodent OA model and promotes the rapid and efficient repair of sheep osteoarthritic critical-size cartilage defects, as well as the reversal of osteoarthritic progression within 6 months. The proposed strategy of locally sustaining H-mediated preservation of transplanted chondrocytes in the pathological microenvironment opens new opportunities to enhance cell transplantation outcomes.
Tumors are increasingly recognized as a consequence of systemic immune dysregulation, while current therapies merely focus on direct tumor killing or local immune activation, overlooking the systemic immune landscape tha...Tumors are increasingly recognized as a consequence of systemic immune dysregulation, while current therapies merely focus on direct tumor killing or local immune activation, overlooking the systemic immune landscape that enables tumorigenesis and metastasis. Targeting distal immune organs, such as the bone marrow (BM), without perturbing tumors remains challenging. Here, we develop a BM-targeted and tumor-evasive cell vector that restricts immunomodulation to the BM niche, enabling systemic immune reprogramming through niche-derived signaling. This mesenchymal stem cell (MSC)-based vector overexpresses Golgi apparatus protein 1 (MSC) to mimic BM affinity signals. In a myelosuppression model, MSC delivers CDK4/6 inhibitors (CDK4/6i) to protect hematopoietic stem and progenitor cells (HSPCs) from chemotherapy toxicity while preserving antitumor efficacy. In a subcutaneous tumor model, MSC delivers interleukin-7 (IL-7), restoring immune competence without promoting tumor proliferation. This strategy establishes a versatile framework for targeted immunomodulation to treat cancer as a systemic immune disease.
Lohbihler M, Lim AA, Massé S
… +18 more, Murareanu BM, Kwan M, Mourad O, Mastikhina O, Elbatarny M, Sarao R, Qiang B, Dhahri W, Chang ML, Xu ALY, Suthiwanich K, Chen M, Mazine A, Khattak S, Nunes SS, Nanthakumar K, Laflamme MA, Protze S
The atrioventricular node (AVN) ensures synchronized heart contractions by establishing the electrical connection between the atria and ventricles. Dysfunction of the pacemaker cells of the AVN leads to atrioventricular...The atrioventricular node (AVN) ensures synchronized heart contractions by establishing the electrical connection between the atria and ventricles. Dysfunction of the pacemaker cells of the AVN leads to atrioventricular block (AV block), a life-threatening condition managed with electronic pacemakers (EPMs). EPMs have drawbacks that could potentially be overcome by a human pluripotent stem cell (hPSC)-derived biological conduction bridge (BioCB). Recent studies demonstrated the differentiation of AVN-like cells from hPSCs, but their conduction properties upon engraftment in vivo remain unexplored. Here, we report the generation of AVN-like pacemaker cells (AVNLPCs) from hPSCs using Wnt and BMP signaling modulation. These AVNLPCs transcriptionally resemble fetal AVN pacemaker cells, exhibit pacemaker action potentials, and display unique AVN-like conduction properties. Notably, when transplanted into the guinea pig heart, AVNLPCs replicate the functional properties of the AVN. Our study highlights the potential of an AVNLPC-based BioCB as a novel cell therapy to improve treatment for patients with AV block.
Kamimae-Lanning AN, Brown JM, Günther M
… +20 more, Esau F, Russell H, Larcher L, Langevin F, Isobe T, Wilson NK, Dingler FA, Cordell RL, Wang M, Millington CL, Claudino N, Gogola E, Nicholls M, Körber V, Göttgens B, de Bruijn MFTR, Garaycoechea JI, Soulier J, Höfer T, Patel KJ
Cell Stem Cell
· 2026 Apr · PMID 41875892
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DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes...DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial for embryonic HSC emergence and throughout life. Despite severe deficiencies in HSCs, these mice produced blood for many months. To determine what enables this, we employed an unbiased method for detecting clones, which exploits somatic variant data. This revealed initial polyclonal hematopoiesis that diminishes to monoclonal hematopoiesis, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to the last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.
The blood-brain barrier (BBB) is essential for maintaining the homeostasis of the central nervous system. However, the processes of BBB formation in humans remain unclear. Here, using single-cell spatiotemporal transcrip...The blood-brain barrier (BBB) is essential for maintaining the homeostasis of the central nervous system. However, the processes of BBB formation in humans remain unclear. Here, using single-cell spatiotemporal transcriptomics, we investigate human BBB development from 6 to 21 gestational weeks (GWs) and observe widespread expression of BBB-specific transporters in all brain-endothelial subclusters during development. We determine the onset of the human BBB-like transcriptional signature at GW8 and prove that neural cells can induce the expression of BBB-specific transporters in brain endothelial cells (ECs) via CADHERIN-2 (CDH2). We also demonstrate that neural progenitor cells promote the proliferation of mural cells. Concomitant with the initiation of the BBB-like transcriptional signature, communication signals between ECs and mural cells begin to intensify. In addition, we reveal conserved BBB development between humans and mice and demonstrate that H2A.Z.1 regulates angiogenesis and BBB development. Collectively, these findings provide unique insights into understanding human BBB ontogeny and identifying therapeutic targets for BBB-related disorders.
Hearing loss has been considered as potentially the leading modifiable risk factor for cognitive decline and dementia, but the causal link between these two conditions remains unsolved. Here, we report that mice with spe...Hearing loss has been considered as potentially the leading modifiable risk factor for cognitive decline and dementia, but the causal link between these two conditions remains unsolved. Here, we report that mice with specific ablation of cochlear outer hair cells display marked hearing loss, which in turn leads to cognitive impairment and defective adult hippocampal neurogenesis. Furthermore, we discover that the dentate gyrus receives auditory input through a neuraxis, which originates from glutamatergic neurons of the caudal pontine reticular nucleus (PnC) and relays via norepinephrinergic neurons of the locus coeruleus (LC). Hearing loss diminishes PnC to LC neuronal afferents, thereby reducing norepinephrine levels. Notably, stimulating PnC to LC neuronal afferents rescues the defective neurogenesis and cognitive impairment caused by hearing loss. Therefore, our study establishes a causal relationship between hearing loss and cognitive decline and emphasizes the importance of hearing wellness in sustaining cognitive function.
Mosti F, Liu J, Lam K
… +9 more, Dillon NR, Skavicus S, Kapps VA, Gjoni K, Lee CF, Glidewell EN, Heaton NS, Pollard KS, Silver DL
Cell Stem Cell
· 2026 Apr · PMID 41861825
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Full text
Genomic modifications underlie the evolution of human brain features, including a larger neocortex. Human accelerated regions (HARs) are highly conserved loci containing human-specific variants, with ∼50% identified as n...Genomic modifications underlie the evolution of human brain features, including a larger neocortex. Human accelerated regions (HARs) are highly conserved loci containing human-specific variants, with ∼50% identified as neurodevelopmental enhancers. However, the neurodevelopmental functions of HARs and their mechanisms of gene regulation are largely unknown. We show that human (Homo sapiens [Hs]) HAR1984 promotes neurogenesis by influencing species-specific transcription and chromatin interactions. Hs-HAR1984 knockin chimpanzee (Pan troglodytes [Pt]) cortical organoids contain more progenitors and neurons, whereas Pt-HAR1984 knockin human cortical organoids exhibit the opposite phenotype. Hs-HAR1984 knockin mice have increased neurogenesis and a thicker cortex with focal folds. HAR1984 exhibits chromatin looping with its target genes, ETV5 and TRA2B, in human fetal brains, which is notably reduced in chimpanzee, macaque, and mouse neural cells. We show that human-specific HAR1984 promotes these interactions and that human-specific ETS variant transcription factor 5 (ETV5) binding auto-regulates enhancer activity. Our study demonstrates molecular mechanisms underlying human-specific neurodevelopment, linking HARs to chromatin architecture, cortical fate, and expansion.