Induced hepatic (iHep) cells generated by direct reprogramming have been proposed as cell sources for drug screening and regenerative medicine. However, the practical use of a 3D hepatic tissue ...culture comprised of iHep cells for drug screening and toxicology testing has not been demonstrated. In this study, a 3D vascularized liver organoid composed of iHep cells and a decellularized liver extracellular matrix (LEM) cultured in a microfluidic system is demonstrated. iHep cells are generated by transfection with polymer nanoparticles and plasmids expressing hepatic transcription factors. The iHep cells are cocultured with endothelial cells in the 3D LEM hydrogel in a microfluidic‐based cell culture device with a continuous dynamic flow of media. The resultant 3D vascularized liver organoids maintained under this physiologically relevant culture microenvironment exhibit improved hepatic functionalities, metabolic activity, biosynthetic activity, and drug responses. Finally, the feasibility of using the iHep‐based 3D liver organoid as a high‐throughput drug screening platform, as well as its use in a multiorgan model comprised of multiple internal organoids is confirmed. The study suggests that a combined strategy of direct reprogramming, matrix engineering, and microfluidics can be used to develop a highly functional, standardized, drug screening, and toxicological analysis platform.
A combined strategy of direct reprogramming, matrix engineering, and microfluidics is used to generate 3D vascularized liver organoids for a drug screening platform. Under the continuous flow of media, the 3D vascularized liver organoids show improved hepatic functionalities and drug responses. The feasibility for a high‐throughput drug screening and an integrated drug testing comprised of multiple organoids is also demonstrated.
Self-polymerized dopamine is a versatile coating material that has various oxygen and nitrogen functional groups. Here, we demonstrate the redox-active properties of self-polymerized dopamine on the ...surface of few-walled carbon nanotubes (FWNTs), which can be used as organic cathode materials for both Li- and Na-ion batteries. We reveal the multiple redox reactions between self-polymerized dopamine and electrolyte ions in the high voltage region from 2.5 to 4.1 V vs. Li using both density functional theory (DFT) calculations and electrochemical measurements. Free-standing and flexible hybrid electrodes are assembled using a vacuum filtration method, which have a 3D porous network structure consisting of polydopamine coated FWNTs. The hybrid electrodes exhibit gravimetric capacities of ∼133 mA h g −1 in Li-cells and ∼109 mA h g −1 in Na-cells utilizing double layer capacitance from FWNTs and multiple redox-reactions from polydopamine. The polydopamine itself within the hybrid film can store high gravimetric capacities of ∼235 mA h g −1 in Li-cells and ∼213 mA h g −1 in Na-cells. In addition, the hybrid electrodes show a high rate-performance and excellent cycling stability, suggesting that self-polymerized dopamine is a promising cathode material for organic rechargeable batteries.
Oxygen‐redox‐based cathode materials for sodium‐ion batteries (SIBs) have attracted considerable attention in recent years owing to the possibility of delivering additional capacity in the ...high‐voltage region. However, they still suffer from not only fast capacity fading but also poor rate capability. Herein, P2‐Na0.75Li0.15Ni0.15Mn0.7O2 is introduced, an oxygen‐redox‐based layered oxide cathode material for SIBs. The effect of Ni doping on the electrochemical performance is investigated by comparison with Ni‐free P2‐Na0.67Li0.22Mn0.78O2. The Na0.75Li0.15Ni0.15Mn0.7O2 delivers a specific capacity of ≈160 mAh g−1 in the voltage region of 1.5–4.6 V at 0.1 C in Na cells. Combined experiments (galvanostatic cycling, neutron powder diffraction, X‐ray absorption spectroscopy, X‐ray photoelectron spectroscopy, and nuclear magnetic resonance (7Li NMR)) and theoretical studies (density functional theory calculations) confirm that Ni substitution not only increases the operating voltage and decreases voltage hysteresis but also improves the cycling stability by reducing Li migration from transition metal to Na layers. This research demonstrates the effect of Li and Ni co‐doping in P2‐type layered materials and suggests a new strategy of using Mn‐rich cathode materials via oxygen redox with optimization of doping elements for SIBs.
The role of Ni substitution on the structure and electrochemical properties of oxygen‐redox‐based P2‐type Na0.67Li0.22Mn0.78O2 layered cathode materials is investigated. Ni provides not only an increase of the operating voltage and decrease of voltage hysteresis, but also improves the cycling stability by reducing Li migration from transition metal to Na layers.
Nonalcoholic fatty liver disease (NAFLD) has been associated with relative skeletal muscle mass in several cross‐sectional studies. We explored the effects of relative skeletal muscle mass and ...changes in relative muscle mass over time on the development of incident NAFLD or the resolution of baseline NAFLD in a large, longitudinal, population‐based 7‐year cohort study. We included 12,624 subjects without baseline NAFLD and 2943 subjects with baseline NAFLD who underwent health check‐up examinations. A total of 10,534 subjects without baseline NAFLD and 2631 subjects with baseline NAFLD were included in analysis of changes in relative skeletal muscle mass over a year. Subjects were defined as having NAFLD by the hepatic steatosis index, a previously validated NAFLD prediction model. Relative skeletal muscle mass was presented using the skeletal muscle mass index (SMI), a measure of body weight–adjusted appendicular skeletal muscle mass, which was estimated by bioelectrical impedance analysis. Of the 12,624 subjects without baseline NAFLD, 1864 (14.8%) developed NAFLD during the 7‐year follow‐up period. Using Cox proportional hazard analysis, compared with the lowest sex‐specific SMI tertile at baseline, the highest tertile was inversely associated with incident NAFLD (adjusted hazard ratio AHR = 0.44, 95% confidence interval CI = 0.38‐0.51) and positively associated with the resolution of baseline NAFLD (AHR = 2.09, 95% CI = 1.02‐4.28). Furthermore, compared with the lowest tertile of change in SMI over a year, the highest tertile exhibited a significant beneficial association with incident NAFLD (AHR = 0.69, 95% CI = 0.59‐0.82) and resolution of baseline NAFLD (AHR = 4.17, 95% CI = 1.90‐6.17) even after adjustment for baseline SMI. Conclusion: Increases in relative skeletal muscle mass over time may lead to benefits either in the development of NAFLD or the resolution of existing NAFLD.
Background and Aims
Following mild liver injury, pre‐existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells ...(BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC‐driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end‐stage liver diseases. Despite this attention, the molecular basis of BEC‐driven liver regeneration remains poorly understood.
Approach and Results
By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC‐driven liver regeneration. Here we show that FXR activation blocks the process through the FXR‐PTEN (phosphatase and tensin homolog)–PI3K (phosphoinositide 3‐kinase)–AKT‐mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC‐to‐hepatocyte differentiation, but not BEC‐to‐LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena/b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC‐driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K‐AKT‐mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC‐driven liver regeneration, as did FXR activation.
Conclusions
FXR activation impairs BEC‐driven liver regeneration by enhancing PTEN activity; the PI3K‐AKT‐mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.
Mesenchymal stromal/stem cells (MSCs) have been developed as a promising source for cell‐based therapies of ischemic disease. However, there are some hurdles in their clinical application such as ...poor cell engraftment and inconsistent stem cell potency. In this study, we sought to find biomarkers for predicting potency of MSCs for proangiogenic therapy to improve their beneficial effects. Large variations were observed in proangiogenic factor secretion profiles of conditioned media derived from nine different donor‐derived Wharton's jelly (WJ)‐derived MSCs and 8 factors among 55 angiogenesis‐related factors were secreted at considerable levels. Two distinct WJ‐MSCs that had the lowest or the highest secretion of these eight factors showed corresponding proangiogenic activities in in vitro angiogenesis assays. When four additional different donor‐derived WJ‐MSCs were further examined, proangiogenic activities in migration and tube formation of endothelial cells and in in vivo Matrigel plug assay were highly consistent with secretion levels of four major factors (angiogenin, interleukin‐8, monocyte chemoattractant protein‐1, and vascular endothelial growth factor). Such correlation was also observed in vascular regenerative effect in a mouse hind limb ischemia model. Blocking of these four factors by neutralizing antibodies or knockdown of them by siRNA treatment resulted in significant inhibition of proangiogenic activities of not only WJ‐MSCs, but also bone marrow‐derived MSCs. These results suggest that these four factors may represent efficient biomarkers for predicting vascular regenerative efficacy of MSCs. Stem Cells 2019;37:77–88
Heterogeneity in the secretome profiles of mesenchymal stromal/stem cells (MSCs) derived from different donors or tissues results in inconsistent stem cell potency. A minimal set of proangiogenic factors consisting of angiogenin, IL‐8, MCP‐1, and vascular endothelial growth factor that are selected from this study is proposed as efficient biomarkers for predicting vascular regenerative efficacy in the treatment of ischemic disease. These biomarkers will be helpful for manufacturing stem cells that are reproducibly effective in the clinic.
Objectives The goal of this study was to identify clinical and lesion-specific local factors affecting visual-functional mismatch. Background Although lesion severity determined by coronary ...angiography has not been well correlated with physiological significance, the mechanism of the discordance remains poorly understood. Methods The authors assessed quantitative coronary angiography, intravascular ultrasound (IVUS), and fractional flow reserve (FFR) in a prospective cohort of 1,000 patients with 1,129 coronary lesions. Three-dimensional computational simulation studies were performed. Results Lesions with angiographic diameter stenosis (DS) ≥50% and FFR >0.80 (“mismatches”) were seen in 57% of non–left main lesions and in 35% of the left main lesions, respectively (p = 0.032). Conversely, among the lesions with DS <50% and FFR <0.80 (“reverse mismatches”) 16% were found in the non–left main lesions and 40% in the left main lesions (p < 0.001). The independent predictors for mismatch were advanced age, non–left anterior descending artery location, absence of plaque rupture, short lesion length, large minimal lumen area, smaller plaque burden, and greater minimal lumen diameter. Conversely, reverse mismatch was independently associated with younger age, left anterior descending artery location, the presence of plaque rupture, a smaller minimal lumen area, and larger plaque burden. In a computational simulation study, FFR was influenced by DS, lesion length, different lesion shape, plaque eccentricity, surface roughness, and various shapes of plaque rupture. Conclusions There were high frequencies of visual-functional mismatch between angiography and FFR. The discrepancy was related to the clinical and lesion-specific factors frequently unrecognizable by angiography, thus suggesting that coronary angiography cannot accurately predict FFR. (Natural History of FFR-Guided Deferred Coronary Lesions IRIS FFR-DEFER; NCT01366404 )
Two trials enrolled a total of 2701 patients who had undergone implantation of a drug-eluting coronary stent and had been receiving dual antiplatelet therapy for at least 12 months. They were ...randomly assigned to either continuation or discontinuation of clopidogrel therapy. At 19.2 months after randomization, the rate of myocardial infarction or death from cardiac causes did not differ significantly between the two groups.
Patients who had undergone implantation of a drug-eluting coronary stent and had been receiving dual antiplatelet therapy for at least 12 months were randomly assigned to either continuation or discontinuation of clopidogrel therapy. At 19.2 months after randomization, the rate of myocardial infarction or death from cardiac causes did not differ significantly between the two groups.
Several pivotal clinical trials have shown that the use of drug-eluting coronary stents is associated with significant reductions in the risks of restenosis and need for target-lesion revascularization, as compared with use of bare-metal coronary stents.
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On the basis of the results of these trials, drug-eluting stents have been widely used for percutaneous coronary intervention (PCI) in clinical practice.
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However, some longer-term studies have shown that drug-eluting stents, as compared with bare-metal stents, are associated with increased rates of late stent thrombosis, death, or myocardial infarction.
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It has been proposed that the occurrence of late clinical events may be . . .
BACKGROUND:Procedural results for percutaneous coronary intervention (PCI) in coronary vessels with chronic total occlusion (CTO) have improved in recent years, and PCI strategies have moved toward ...more complete revascularization with more liberal use of CTO-PCI. However, evidence evaluating CTO-PCI is limited to observational studies and small clinical trials.
METHODS:In this open-label, multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either 1 of 2 strategiesPCI or no PCI for the qualifying de novo CTO lesion with the option for PCI of obstructive non-CTO lesions at the discretion of the operator. The primary end point was a composite of death, myocardial infarction, stroke, or any revascularization. Health-related quality of life was assessed at baseline and at 1, 6, 12, 24, and 36 months. Because of slow recruitment, the trial was stopped before completion of the 1284 planned enrollments.
RESULTS:Between March 2010 and September 2016, 834 patients were randomly assigned to the CTO-PCI (n=417) or no CTO-PCI (n=398) strategy. Among the patients assigned to the no CTO-PCI strategy, 78 (19.6%) crossed over to receive staged CTO-PCI within 3 days of randomization. The overall CTO-PCI success rate was 90.6%. Serious nonfatal complications associated with CTO-PCI occurred in 3 patients (1 stroke, 1 cardiac tamponade, and 1 patient with recurrent episodes of ventricular tachyarrhythmia induced by intracoronary thrombus). Approximately half of the patients in each group underwent PCI for an average of 1.3 non-CTO lesions, resulting in a comparable residual SYNTAX score (Synergy Between PCI With TAXUS and Cardiac Surgery; 3.7±5.4 versus 4.0±5.9, P=0.42) confined to non-CTO vessels. During a median follow-up of 4.0 years (interquartile range, 2.4 to 5.1 years), there was no significant difference between the CTO-PCI and the no CTO-PCI strategies in the incidence of the primary end point (22.3% versus 22.4%, hazard ratio, 1.03; 95% CI, 0.77 to 1.37; P=0.86). Both CTO-PCI and no CTO-PCI strategy were associated with significant improvements but without between-group differences in disease-specific health status that was sustained through 36 months.
CONCLUSIONS:CTO-PCI was feasible with high success rates. There was no difference in the incidence of major adverse cardiovascular events with CTO-PCI versus no CTO-PCI, but the study was limited by low power for clinical end points and high crossover rates between groups.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01078051.
Intense table‐top terahertz (THz) sources, which have progressed tremendously in the last decade, are becoming more important for advanced THz science to study light–matter interactions and ...subsequent applications. Nonlinear optical organic crystals exhibit great potential for intense broadband THz wave generation due to their large nonlinearities and advantageous phase‐matching characteristics. However, the phonon‐induced absorption of most organic crystals in the THz region leads to undesired modulation of the spectrum and limits the THz output efficiency. To overcome such drawbacks, phonon‐mode engineering by modification of molecular structures is suggested, but intrinsic limitations still remain. Here, an efficient alternative approach has been recently proposed for generating intense broadband THz waves based on a tandem configuration that combines two complementary nonlinear organic crystals. Such configuration compensates for the spectral gap of the generated THz waves mainly caused by phonon absorption and additionally enhances the optical‐to‐THz conversion efficiency. The proposed organic tandem generator indicates a substantial enhancement of the peak‐to‐peak THz electric field due to effective spectral filling at phonon absorption gaps. As a result, such tandem configuration provides a versatile platform to generate gapless broadband THz spectra with suppressed phonon absorption and contributes to advancing the development of intense broadband coherent THz sources.
The proposed tandem configuration of organic crystals as an alternative approach for efficient generation of intense broadband THz waves provides enhanced THz electric fields and substantially improved spectral distribution at the phonon‐induced absorption gap by effective spectral filling through combining two complementary nonlinear optical organic crystals.
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