Biology subjects

Feng, L.

Publications and source records attributed to Feng, L..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Divergent roles of SOX2 in human and mouse germ cell specification related to X-linked gene dosage effects

Human primordial germ cell-like cells (hPGCLCs) can be generated from pluripotent stem cells (PSCs) but the differentiation efficiency of female hPSCs is often lower than that of male hPSCs. Moreover, Klinefelter Syndrome (KS), a condition characterized by an extra X-chromosome in males, often presents the failure of germline specification and infertility. In this study, we investigate how X-linked gene dosage affects hPGCLCs specification potential in both healthy and diseased conditions. We reveal that the X-chromosome plays a multifaceted role in modulating hPGCLCs induction. The inhibitory effects on TGF-beta/Activin A and BMP pathways by escape genes IGSF1 and CHRDL1, respectively, are demonstrated by the increased yield of hPGCLCs with knockdown experiments. Importantly, our results identified the intriguing role of SOX2 that is upregulated by the escape gene USP9X in hPGCLCs specification, highlighting a species-specific difference from the mouse model. The elevated USP9X-SOX2 regulatory axis profoundly influences cellular metabolism, mitochondrial morphology, and progenitor competence, thereby affecting hPGCLCs induction. Furthermore, the inability to downregulate SOX2 and upregulate SOX17 in response to BMP signaling impedes downstream gene activation due to motif binding competition. These findings shed novel insights into the hPGC specification by elucidating the differential roles of SOX2 versus SOX17 between mice and humans, influenced by X-linked gene dosage effects. Additionally, our results offer potential applications for improving the induction and survival efficiency of hPGCLCs from hPSCs, facilitating disease modeling and mechanistic studies. HighlightsO_LIDownregulation of three X-linked genes, i.e. IGSF1, CHRDL1 and USP9X, enhanced the differentiation efficiency of hPGCLCs C_LIO_LISOX2 as a downstream of human-specific escape gene USP9X plays a multifacet role against hPGCLCs specification C_LIO_LIFailure to timely downregulate SOX2 and upregulate SOX17 interferes downstream gene activation likely due to motif binding competition C_LI

cell biology↗

bioRxiv2024

A generalized framework to identify SARS-CoV-2 broadly neutralizing antibodies

Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 receptor-binding domain (RBD) are used to treat and prevent COVID-19. However, the rapid evolution of SARS-CoV-2 drives continuous escape from therapeutic mAbs. Therefore, the ability to identify broadly neutralizing antibodies (bnAbs) against future variants is needed. Here, we use deep mutational scanning (DMS) to predict viral RBD evolution and to select for mAbs neutralizing both existing and prospective variants. A retrospective analysis of 1,103 SARS-CoV-2 wildtype-elicited mAbs shows that this method can increase the probability of identifying effective bnAbs against the XBB.1.5 strain from 1% to 40% in an early pandemic setup. Among these bnAbs, BD55-1205 exhibited potent activity against all tested variants. Cryo-EM structural analyses revealed the receptor mimicry of BD55-1205, explaining its broad reactivity. Delivery of mRNA-LNPs encoding BD55-1205-IgG in mice resulted in ~5,000 serum NT50 against XBB.1.5, HK.3.1, and JN.1 variants. Combining bnAb identification using viral evolution prediction with the versatility of mRNA delivery technology can enable rapid development of next-generation antibody-based countermeasures against SARS-CoV-2 and potentially other pathogens with pandemic potential.

immunology↗

bioRxiv2023

mRNA Vaccines Encoding Influenza Virus Hemagglutinin (HA) Elicits Immunity in Mice from Influenza A Virus Challenge

Influenza viruses cause epidemics and can cause pandemics with substantial morbidity with some mortality every year. Seasonal influenza vaccines have incomplete effectiveness and elicit a narrow antibody response that often does not protect against mutations occurring in influenza viruses. Thus, various vaccine approaches have been investigated to improve safety and efficacy. Here, we evaluate an mRNA influenza vaccine encoding hemagglutinin (HA) proteins in a BALB/c mouse model. The results show that mRNA vaccination elicits neutralizing and serum antibodies to each influenza virus strain contained in the current quadrivalent vaccine that is designed to protect against four different influenza viruses including two influenza A viruses (IAV) and two influenza B (IBV), as well as several antigenically distinct influenza virus strains in both hemagglutination inhibition assay (HAI) and virus neutralization assays. The quadrivalent mRNA vaccines had antibody titers comparable to the antibodies elicited by the monovalent vaccines to each tested virus regardless of dosage following an mRNA booster vaccine. Mice vaccinated with mRNA encoding an H1 HA had decreased weight loss and decreased lung viral titers compared to mice not vaccinated with an mRNA encoding an H1 HA. Overall, this study demonstrates the efficacy of mRNA-based seasonal influenza vaccines are their potential to replace both the currently available split-inactivated, and live-attenuated seasonal influenza vaccines.

immunology↗

bioRxiv2023

Identification of avaC from infant gut microbial isolates that convert 5AVA to 2-piperidone with high efficiency

2-Piperidone has been identified as a biomarker for various human diseases, but its origin in vivo remains poorly understood. Furthermore, 2-piperidone is a crucial industrial raw material, and thus the discovery of novel efficient 2-piperidone synthases may have an important application in its biosynthesis. In this study, we aimed to identify the bacterial source and metabolic mechanism of 2-piperidone from a previously generated infant gut microbial culture collection. We found that 2-piperidone could be produced from 5AVA by four bacterial strains, including Collinsella aerofaciens LFYP39, Collinsella intestinalis LFYP54, Clostridium bolteae LFYP116, and Clostridium hathewayi LFYP18 from 51 bacterial strains. Furthermore, 2-piperidone could be synthesized from proline by cross-feeding between Clostridium difficile LFYP43 and Collinsella intestinalis LFYP54. We employed a gain-of-function library to identify the gene avaC (5-aminovaleric acid cyclase) which can catalyze 5AVA to produce 2-piperidone in C. intestinalis LFYP54. Homologous genes of avaC were also identified and validated in the other three bacterial strains. Gene avaC exhibits a broad distribution in the natural environmental bacteria. Overall, our research identified the gut bacterial strains and the genes that are responsible for the production of 2-piperidone. This study may facilitate the prediction of 2-piperidone-related disease risks through the analysis of gut bacterial community composition, and enhance the efficiency of 2-piperidone in its biosynthesis in industry. ImportanceIn recent decades, it has become a consensus that gut microbiota can affect host health through producing metabolites. However, the complexity of gut flora composition makes finding the sources of the particular metabolite challenging. 2-piperidone is a biomarker for various diseases and a highly valued raw material for nylons. In this study, we identified the gut bacterial strains that can transform 5AVA to 2-piperidone. A novel 2-piperidone synthase gene, avaC, was also identified and characterized. These findings provided new insights into the potential connection between 2-piperidone related diseases and the intestinal flora, as well as a possible novel approach for more efficient biosynthesis of 2-piperidone in industry.

microbiology↗

bioRxiv2023

APOE4 poses opposite effects of plasma LDL on white matter integrity in older adults

INTRODUCTIONAPOE4 is a strong genetic risk factor of Alzheimers disease and is associated with changes in metabolism. However, the interactive relationship between APOE4 and plasma metabolites on the brain remains largely unknown. MEHODSIn the UK Biobank, we investigated the moderation effects of APOE4 on the relationship between 249 plasma metabolites derived from nuclear magnetic resonance spectroscopy on whole-brain white matter integrity, measured by fractional anisotropy using diffusion magnetic resonance imaging. RESULTSThe increase in the concentration of metabolites, mainly LDL and VLDL, is associated with a decrease in white matter integrity (b= -0.12, CI= [-0.14, -0.10]) among older APOE4 carriers, whereas an increase (b= 0.05, CI= [0.04, 0.07]) among non-carriers, implying a significant moderation effect of APOE4 (b= -0.18, CI= [-0.20,-0.15]). DISCUSSIONThe results suggest that lipid metabolism functions differently in APOE4 carriers compared to non-carriers, which may inform the development of targeted interventions for APOE4 carriers to mitigate cognitive decline.

neuroscience↗

bioRxiv2023

Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation

Chromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their mechanistic roles in development remain unclear. Here we focus on dominant mutations affecting histone H4 lysine 91. These H4K91 mutants form aberrant nuclear puncta at specific heterochromatin regions. Mechanistically, H4K91 mutants demonstrate enhanced binding to the histone variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminishes the mutant localization to chromatin. Our functional studies demonstrate that H4K91 mutant expression increases chromatin accessibility, alters developmental gene expression through accelerating pro-neural differentiation, and causes reduced mouse brain size in vivo, reminiscent of the microcephaly phenotypes of patients. Together, our studies unveil a distinct molecular pathogenic mechanism from other known histone mutants, where H4K91 mutants misregulate cell fate during development through abnormal genomic localization.

molecular biology↗

bioRxiv2023

Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted IL-22 production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells (DCs) and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

physiology↗

bioRxiv2023

Elucidating the role of water in collagen self assembly by isotopically modulating collagen hydration

Water is known to play an important role in collagen self assembly, but it is still largely unclear how water-collagen interactions influence the assembly process and determine the fibril network properties. Here, we use the H2O/D2O isotope effect on the hydrogen-bond strength in water to investigate the role of hydration in collagen self assembly. We dissolve collagen in H2O and D2O, and compare the growth kinetics and the structure of the collagen assemblies formed in these water isotopomers. Surprisingly, collagen assembly occurs ten times faster in D2O than in H2O, and collagen in D2O self assembles into much thinner fibrils, that form a more inhomogeneous and softer network, with a fourfold reduction in elastic modulus compared to H2O. Combining spectroscopic measurements with atomistic simulations, we show that collagen in D2O is less hydrated than in H2O. This partial dehydration lowers the enthalpic penalty for water removal and reorganization at the collagen-water interface, increasing the self assembly rate and the number of nucleation centers, leading to thinner fibrils and a softer network. Coarse-grained simulations show that the acceleration in the initial nucleation rate can be reproduced by the enhancement of electrostatic interactions, which appear to be crucial in determining the acceleration of the initial nucleation rate. These results show that water acts as a mediator between collagen monomers, by moderating their interactions so as to optimize the assembly process and, thus, the final network properties. We believe that isotopically modulating the hydration of proteins can be a valuable method to investigate the role of water in protein structural dynamics and protein self assembly.

biophysics↗

bioRxiv2023

Living cell mTORC1 inhibition reporter mTIR reveals nutrient-sensing targets of histone deacetylase inhibitor

Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is a clinically effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration, yet an efficient tool to monitor mTORC1 inhibition in living cells or tissues is still lacking. Here we devised a genetically encoded mTORC1 inhibition reporter termed mTIR that exhibits a highly contrasted fluorescence puncta pattern in response to mTORC1 inhibition. mTIR specifically senses physiological, pharmacological and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, mTIR can be applied as an powerful tool for imaging-based visual screening of mTORC1 inhibitors. By this method, we identified histone deacetylase inhibitors (HDACi) that selectively inhibit mTORC1 by inducing nutrient-sensing gene expression. Thus, mTIR is a unique living cell reporter efficiently detecting the inhibition of mTORC1 activity, and the HDACi Panobinostat transcriptionally target mTORC1 signaling via amino acids sensing.

cell biology↗

bioRxiv2023

Pathogen protein modularity enables elaborate mimicry of a host phosphatase

Pathogens produce diverse effector proteins to manipulate host cellular processes. However, how functional diversity is generated in an effector repertoire is poorly understood. Many effectors in the devastating plant pathogen Phytophthora contain tandem repeats of the "(L)WY" motif, which are structurally conserved but variable in sequences. Here, we discovered a functional module formed by a specific (L)WY-LWY combination in multiple Phytophthora effectors, which efficiently recruit the Serine/Threonine protein phosphatase 2A (PP2A) core enzyme in plant hosts. Crystal structure of an effector-PP2A complex shows that the (L)WY-LWY module enables hijacking of the host PP2A core enzyme to form functional holoenzymes. While sharing the PP2A-interacting module at the amino terminus, these effectors possess divergent C-terminal LWY units and regulate distinct sets of phosphoproteins in the host. Our results highlight the appropriation of an essential host phosphatase through molecular mimicry by pathogens and diversification promoted by protein modularity in an effector repertoire.

plant biology↗

bioRxiv2023

Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal IgA response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal sIgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies targeting the receptor-binding domain of the spike protein (01A05, rmAb23, DXP-604 and XG014). Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2 and BA.4/5 with a 50-150-fold increase in potency, reaching the level of the most potent monoclonal antibodies described till date. In hACE2 transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Conversion of IgA and dimerization further enhanced or restored the neutralizing ability against the emerging Omicron sub-variants (DXP-604 for BQ.1, BQ.1.1 and BA2.75; 01A05 for BA2.75, BA.2.75.2 and XBB.1). Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by subvariants and, potentially, future VOCs. One Sentence SummaryEngineered dimeric and secretory IgA1 neutralized Omicron variant with higher potency than parental IgG.

microbiology↗

bioRxiv2023

Cell type-specific responses to fungal infection in plants revealed by single-cell transcriptomics

Plant infection by microbial pathogens is a dynamic process. Here, we investigated the heterogeneity of plant responses in the context of pathogen location. A single-cell atlas of Arabidopsis thaliana leaves challenged by the fungus Colletotrichum higginsianum revealed cell type-specific gene expression that highlights an enrichment of intracellular immune receptors in vasculature cells. Using trajectory inference, we assigned cells that directly interacted with the invasive hyphae. Further analysis of cells at these infection sites revealed transcriptional plasticity based on cell type. A reprogramming of abscisic acid signalling was specifically activated in guard cells. Consistently, a contact-dependent stomatal closure was observed, possibly representing a defense response that anticipates pathogen invasive growth. We defined cell type-specific deployments of genes activating indole glucosinolate biosynthesis at the infection sites, and determined their contribution to resistance. This research highlights the spatial dynamics of plant response during infection and reveals cell type-specific processes and gene functions.

plant biology↗

bioRxiv2023

Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stresses

Accumulating evidences indicate that acetate is increased in energy stresses such as diabetes mellitus and prolonged starvation. However, it is largely unknown how and where acetate is produced and what is its biological significance. We observed overproduction of acetate in an amount comparable to ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT 12&8 are dramatically upregulated in liver to convert FFA-derived acetyl-CoA to acetate and CoA. This conversion not only provides large amount of acetate which fuels brain preferentially rather than muscle, but also recycles CoA which is required for sustained fatty acid oxidation and ketogenesis. Taken together, we suggest that acetate is an emerging novel "ketone body" and may be used as a parameter to evaluate the progression of energy stress in the future.

biochemistry↗

bioRxiv2023

Tumour Extracellular Vesicles Induce Neutrophil Extracellular Traps To Promote Lymph Node Metastasis

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities. Graphic AbstractIllustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/532413v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@c0c371org.highwire.dtl.DTLVardef@15f6a92org.highwire.dtl.DTLVardef@14dbeedorg.highwire.dtl.DTLVardef@131d3eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Does the territorial behaviour of the Amur tiger affect the accuracy of occupancy estimation?

1. Accurate estimates of wildlife distributions and population persistence are essential for conservation programs. Occupancy models that account for detection probability have been used to characterize the occupancy and habitat selection of imperilled species. However, failure to distinguish between true-presence and pseudo-presence associated with territorial behaviour can result in the overestimation of the occupancy probability of target species in unsuitable habitats, and this can have major implications for the development of conservation strategies. 2. For highly territorial wildlife species requiring high-quality habitat for survival, occasional Presence in unsuitable areas might be related to dispersal or migration, but this does not reflect actual occupancy and habitat use. True-Presence and Pseudo-Presence should be distinguished for target species to better reflect their actual occupancy and habitat use. 3. To investigate the effect of True-Presence and Pseudo-Presence on wildlife occupancy estimation, we developed a modified model (Mm) that considers the territorial behaviour of the Amur tiger in northeast China, which distinguished between True-Presence and Pseudo-Presence. We compared two models, Mm and M0 (conventional occupancy model), and assessed model performance using goodness-of-fit evaluation, detection and occupancy probability, and favourable variable selection. 4. We found that Mm, which has fewer favourable variables, is more powerful than M0 for estimating detection and occupancy probability, as well as characterizing the effect of various factors on the habitat use of Amur tigers. Furthermore, Mm significantly reduced the overestimation of occupancy probability outside the home range compared with M0, and detection probability estimates did not significantly differ between M0 and Mm. Finally, Mm provided more empirical habitat selection variables for the Amur tiger. 5. Our results revealed how True-Presence and Pseudo-Presence affect the occupancy probability and habitat selection of Amur tigers. Our method improves the accuracy of occupancy models; it can also be used to characterize the habitat selection and distribution of wildlife species and be applied to other territorial species.

ecology↗

bioRxiv2022

An Iron-Calcium-Miro Axis Influences Parkinson Risk and Neurodegeneration

Dysregulated iron or Ca2+ homeostasis has been reported in Parkinsons disease (PD) models. Here we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with Mitochondrial Calcium Uniporter. In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover FDA-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology, and drug targets and candidates coupled with a convenient stratification method.

cell biology↗

bioRxiv2022

The protist ubiquitin ligase effector PbE3-2 targets RD21A to impede plant immunity

Clubroot caused by the soil-borne protist pathogen Plasmodiophora brassicae is one of the most devastating diseases of Brassica oil and vegetable crops worldwide. Understanding the pathogen infection strategy is crucial for the development of disease control. However, the molecular mechanism by which this pathogen promotes infection remains largely unknown. Here, we identified a P. brassicae-secreted effector PbE3-2 that impedes plant immunity by ubiquitinating the immune regulator RD21A for degradation. Overexpression of PbE3-2 in Arabidopsis thaliana resulted in higher susceptibility to P. brassicae and decreases in chitin-triggered reactive oxygen species burst and expression of marker genes in salicylic acid signaling. PbE3-2 interacted with and ubiquitinated RD21A in vitro and in vivo. Mutant plants deficient in RD21A exhibited similar susceptibility and compromsied immune responses as in PbE3-2 overexpression plants. These results suggest that P. brassicae promotes clubroot disease through RD21A degradation mediated by the effector PbE3-2. As PbE3-2 is widely conserved across different P. brassicae pathotypes, the degradation of RD21A by PbE3-2 might be a prevalent infection strategy in this pathogen.

microbiology↗

bioRxiv2022

Toxicity of microplastics and plastic additive co-exposure in liver Disse organoids from healthy donors and patient-derived induced pluripotent stem cells

The ubiquitous microplastics (MPs) and plastic additives in the environment usually form complexes, enter human blood circulation, and increase the risk of steatohepatitis. The liver Disse space plays a vital role in corresponding hepatic pathological processes. However, due to the limited understanding of the regulatory cues in multilineage maturation, the generation of large-scale Disse-like organoids (DOs) mirroring the comprehensive toxicity responses of MPs is challenging. Here, using human-induced pluripotent stem cells (hiPSCs), we biofabricated healthy donors and patient-derived DOs containing hepatocytes, endothelial cells, and hepatic stellate cells, resembling the features of Disse space. These organoids revealed that polystyrene MPs preferentially entered endothelial cells and then dispersed throughout the organoids, similar to reported studies in zebrafish. Co-exposure to MPs and tetrabromobisphenol A (TBBPA), a common plastic additive, showed enhanced accumulation of contamination in the organoids. We also biofabricated alcoholic liver disease (ALD) patient-derived DOs representing the specific disease transcriptional profiles. We found that co-exposure to MPs and TBBPA at environmental-related dosages significantly elevated the pathological transcriptional expression and biochemical profiles in patient-derived DOs but not in healthy organoids, suggesting that both hereditary factors and pollutants contribute to susceptibility to environmental toxicants. This study exemplified the value of biofabricated hiPSC-derived organoids in environmental toxicology and offered a powerful strategy for personalized toxicology evaluation.

bioengineering↗