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Organoids are three-dimensional (3D) miniature structures cultured in vitro produced from either human pluripotent stem cells (hPSCs) or adult stem cells (AdSCs) derived from healthy individuals or patients that recapitulate the cellular heterogeneity, structure, and functions of human organs. The advent of human 3D organoid systems is now possible to allow remarkably detailed observation of stem cell morphogens, maintenance and differentiation resemble primary tissues, enhancing the potential to study both human physiology and developmental stage. As they are similar to their original organs and carry human genetic information, organoids derived from patient hold great promise for biomedical research and preclinical drug testing and is currently used for personalized, regenerative medicine, gene repair and transplantation therapy. In recent decades, researchers have succeeded in generating various types of organoids mimicking in vivo organs. Herein, we provide an update on current in vitro differentiation technologies of brain, retinal, kidney, liver, lung, gastrointestinal, cardiac, vascularized and multi-lineage organoids, discuss the differences between PSC- and AdSC-derived organoids, summarize the potential applications of stem cell-derived organoids systems in the laboratory and clinic, and outline the current challenges for the application of organoids, which would deepen the understanding of mechanisms of human development and enhance further utility of organoids in basic research and clinical studies.

Numerous studies have used human pluripotent stem cell-derived cerebral organoids to elucidate the mystery of human brain development and model neurological diseases in vitro, but the potential for grafted organoid-based therapy in vivo remains unknown. Here, we optimized a culturing protocol capable of efficiently generating small human cerebral organoids. After transplantation into the mouse medial prefrontal cortex, the grafted human cerebral organoids survived and extended projections over 4.5 mm in length to basal brain regions within 1 month. The transplanted cerebral organoids generated human glutamatergic neurons that acquired electrophysiological maturity in the mouse brain. Importantly, the grafted human cerebral organoids functionally integrated into pre-existing neural circuits by forming bidirectional synaptic connections with the mouse host neurons. Furthermore, compared to control mice, the mice transplanted with cerebral organoids showed an increase in freezing time in response to auditory conditioned stimuli, suggesting the potentiation of the startle fear response. Our study showed that subcortical projections can be established by microtransplantation and may provide crucial insights into the therapeutic potential of human cerebral organoids for neurological diseases.

Skin tissue engineering scaffolds should possess key properties such as porosity, degradability, durability, and biocompatibility to effectively facilitate skin cell adhesion and growth. In this study, recombinant human collagen (RHC) was used to fabricate porous scaffolds via freeze-drying, offering an alternative to animal-derived collagen where bovine collagen (BC)-based scaffolds were also prepared for comparison. The internal morphology of the RHC scaffolds were characterized by scanning electron microscopy (SEM) and the pore size ranged from 68.39 to 117.52 µm. The results from compression and fatigue tests showed that the mechanical strength and durability of RHC scaffolds could be tailored by adjusting the RHC concentration, and the maximum compressive modulus reached to 0.003 MPa, which is comparable to that of BC scaffolds. The degradation test illustrated that the RHC scaffolds had a slower degradation rate compared to BC scaffolds. Finally, the biocompatibilities of the porous scaffolds were studied by seeding and culturing the human foreskin fibroblasts (HFFs) and human umbilical vein endothelial cells (HUVECs) in samples. The fluorescent images and Cell Counting Kit-8 (CCK-8) assay revealed RHC porous scaffolds were non-cytotoxic and supported the attachment as well as the proliferation of the seeded cells. Overall, the results demonstrated that RHC-based scaffolds exhibited adequate mechanical strength, ideal biodegradability, and exceptional biocompatibility, making them highly suitable for skin-tissue-engineering applications.

Major depressive disorder with suicide behavior (sMDD) is a severe mood disorder, bringing tremendous burden to family and society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues of sMDD patients, the molecular mechanism by which GABA levels are altered remains elusive. In this study, we generated induced pluripotent stem cells (iPSC) from five sMDD patients and differentiated the iPSCs to GABAergic interneurons (GINs) and ventral forebrain organoids. sMDD GINs exhibited altered neuronal morphology and increased neural firing, as well as weakened calcium signaling propagation, compared with controls. Transcriptomic sequencing revealed that a decreased expression of serotoninergic receptor 2C (5‐HT2C) may cause the defected neuronal activity in sMDD. Furthermore, targeting 5‐HT2C receptor, using a small molecule agonist or genetic approach, restored neuronal activity deficits in sMDD GINs. Our findings provide a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD. Synopsis iPSC‐derived GABAergic interneurons generated from major depressive disorders with suicide behavior (sMDD) patients exhibit decreased 5‐HT2C expression. Trazodone hydrochloride (Trzd) that targets 5‐HT2C restores neuronal deficits, indicating that 5‐HT2C could be a therapeutic target for sMDD sMDD‐derived GABAergic interneurons (GINs) display altered neuronal morphology and abnormal GIN subtypes. sMDD‐derived GINs show abnormal electrophysiological hyperexcitability and decreased calcium signaling. Transcriptional analysis reveals a low expression level of HTR2C in sMDD‐derived GINs. sMDD‐associated neural defects can be restored by overexpression of HTR2C and 5‐HT 2C R agonist Trzd. Graphical Abstract iPSC‐derived GABAergic interneurons generated from major depressive disorders with suicide behavior (sMDD) patients exhibit decreased 5‐HT2C expression. Trazodone hydrochloride (Trzd) that targets 5‐HT2C restores neuronal deficits, indicating that 5‐HT2C could be a therapeutic target for sMDD.

A novel electrochemical and fluorescence dual-signal assay was developed for the determination of hydrogen peroxide (H 2 O 2 ) based on Fe 3 O 4 @MnO 2 and N-doped carbon dots (NCDs). Fe 3 O 4 @MnO 2 was not only applied as the recognizer for H 2 O 2 but also served as the fluorescence quencher and electrochemical enhancer. This permits the dual-signal readout of the analytical system. In the absence of H 2 O 2 , the NCDs were quenched by Fe 3 O 4 @MnO 2 , and the oxidation of the electrochemical probe ferrocene (Fc) was catalyzed by Fe 3 O 4 @MnO 2 . In the presence of H 2 O 2 , MnO 2 was reduced to Mn 2+ , leading to the fluorescence recovery of NCDs and the reduction in the oxidation signal of Fc. By combining the electrochemical method and the fluorescence assay, more comprehensive and valuable information for H 2 O 2 determination was provided to meet different analytical demands. The method exhibits good repeatability and selectivity with a detection limit of 1.0 μM for the fluorescence assay and 0.6 μM for the electrochemical method. The proposed approach holds great potential for probing released targets from living cells. Graphical abstract

Fatty acid (FA) overload imposes substantial stress on hypothalamic neurons, whilst whether cortical input could improve metabolic resilience of hypothalamic neurons remains poorly understood. Here, we reconstructed human cortical‐hypothalamic assembloids (CO‐HTO assembloids) to investigate how cortical input modulates hypothalamic responses to FA. Our results revealed that FA could impair neuronal survival, α‐MSH secretion, and electrophysiological activity in hypothalamic organoids (HTOs). Remarkably, fusion with cortical organoids (COs) could prevent FA‐induced apoptosis and functional defects, preserve mitochondrial respiration, and reduce lipid accumulation in HTOs. Also, transcriptomic and functional analyses revealed that cortical input could activate PGC1α‐dependent mitochondrial biogenesis. Furthermore, pharmacological PGC1α activation or glutamate treatment rescued the FA‐induced defects in HTOs. Collectively, our findings uncovered a cortico‐hypothalamic regulatory axis and found glutamate‐driven PGC1α activation might maintain hypothalamic neuronal stability and improve resilience to metabolic stress. Our CO‐HTO assembloids provided a promising platform to investigate complex inter‐regional communications and related neurological and metabolic disorders.

Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson’s disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction. Inhibition of EHMT1/2 with the specific inhibitor A-366 or shRNA suppressed histone methylation and alleviated synaptic damage in primary neurons that were treated with PFFs. In addition, the synaptic damage and motor impairment in mice that were injected with PFFs were repressed by treatment with the EHMT1/2 inhibitor A-366. Thus, our findings reveal the role of histone H3 modification by EHMT1/2 in synaptic damage and motor impairment in a PFF animal model, suggesting the involvement of epigenetic dysregulation in PD pathogenesis.

A novel electrochemical and fluorescence dual-signal assay was developed for the determination of hydrogen peroxide (H.sub.2O.sub.2) based on Fe.sub.3O.sub.4@MnO.sub.2 and N-doped carbon dots (NCDs). Fe.sub.3O.sub.4@MnO.sub.2 was not only applied as the recognizer for H.sub.2O.sub.2 but also served as the fluorescence quencher and electrochemical enhancer. This permits the dual-signal readout of the analytical system. In the absence of H.sub.2O.sub.2, the NCDs were quenched by Fe.sub.3O.sub.4@MnO.sub.2, and the oxidation of the electrochemical probe ferrocene (Fc) was catalyzed by Fe.sub.3O.sub.4@MnO.sub.2. In the presence of H.sub.2O.sub.2, MnO.sub.2 was reduced to Mn.sup.2+.sub., leading to the fluorescence recovery of NCDs and the reduction in the oxidation signal of Fc. By combining the electrochemical method and the fluorescence assay, more comprehensive and valuable information for H.sub.2O.sub.2 determination was provided to meet different analytical demands. The method exhibits good repeatability and selectivity with a detection limit of 1.0 [mu]M for the fluorescence assay and 0.6 [mu]M for the electrochemical method. The proposed approach holds great potential for probing released targets from living cells.

A novel electrochemical and fluorescence dual-signal assay was developed for the determination of hydrogen peroxide (H O ) based on Fe O @MnO and N-doped carbon dots (NCDs). Fe O @MnO was not only applied as the recognizer for H O but also served as the fluorescence quencher and electrochemical enhancer. This permits the dual-signal readout of the analytical system. In the absence of H O , the NCDs were quenched by Fe O @MnO , and the oxidation of the electrochemical probe ferrocene (Fc) was catalyzed by Fe O @MnO . In the presence of H O , MnO was reduced to Mn leading to the fluorescence recovery of NCDs and the reduction in the oxidation signal of Fc. By combining the electrochemical method and the fluorescence assay, more comprehensive and valuable information for H O determination was provided to meet different analytical demands. The method exhibits good repeatability and selectivity with a detection limit of 1.0 μM for the fluorescence assay and 0.6 μM for the electrochemical method. The proposed approach holds great potential for probing released targets from living cells. Graphical abstract.

Abstract Background: Without timely and effective rehabilitation, hearing loss may profoundly affect human life quality. China has a large population of hearing-impaired individuals, which imposes a heavy health burden on society. Moreover, this population is projected to increase rapidly owing to China’s aging society. Methods: We used data from a population-representative epidemiological investigation of hearing loss and ear diseases in four Chinese provinces. We estimated the national prevalence using multiple linear regression of the age-group proportions and prevalence in 31 provinces with clustering analysis. We used years lived with disability (YLDs) to analyze the disease burden and forecasted the prevalence of hearing loss by 2060 in China. Results: An estimated 115 million people had moderate-to-complete hearing loss in 2015 across the 31 provinces of China (8.4% of 1.37 billion people). Of these, 85.7% were older than age 50 years (99 million people) and 2.4% were younger than 20 years old (2.8 million people). Of all YLDs attributable to hearing loss, 68.9% were attributable to moderate-to-complete cases. By 2060, a projected 242 million people in China will have moderate-to-complete hearing loss, a 110.0% increase from 2015. Conclusions: The hearing loss prevalence in China is high. Population aging and socioeconomic factors substantially affect the prevalence and severity of hearing loss and the disease burden. The prevalence and severity of hearing loss are unevenly distributed across different provinces. Future public health policies should take these trends and regional variations into account.