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Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.

Excessive phosphate poses a serious ecological and human health risk, and thereby, monitoring its trace concentration is of great significance to environmental protection and human health. In this work, a zirconium–porphyrin framework (PCN-222) with excellent stability and unique luminescence properties was designed to modify the surface of the indium tin oxide electrode, which was first used as a photoelectrochemical (PEC) probe for phosphate detection. The PCN-222-modified PEC probe demonstrated an excellent selectivity and stability and indicated a linear response to phosphate in the range of 0–106nM with a limit of detection (LOD) as low as 1.964 nM. To the best of our knowledge, this is the phosphate probe with the lowest LOD, and this is also the first signal-on PEC probe toward phosphate based on PCN-222. More importantly, the PEC probe can be validated for the good applicability of trace phosphate detection in real water samples, indicating a good application prospect. Finally, a series of electrochemical and spectroscopic studies have proved that phosphate can bind to the indium tin oxide (ITO)/PCN-222 electrode, which shortens the distance of the space charge region while reducing the bandwidth and thus facilitates the transfer of photogenerated electrons across the energy band barrier to reduce O2in the electrolyte, producing an enhanced cathodic photocurrent signal. The proposed strategy of the highly sensitive PEC probe provides a promising platform for more effective label-free phosphate monitoring in the environment and organisms.

C63H63LaO27, trigonal, R3 (no. 146), a= 27.5427(11) Å, c= 7.7330(4) Å, V= 5080.3(5) Å3, Z= 3, Rgt(F) = 0.037, wRref(F2) = 0.096, T= 100 K.

To develop a functional alternative hepatocyte model for primary human hepatocytes (PHHs) with proliferative property, essential drug metabolic, and transporter functions, proliferating human hepatocytes (ProliHHs) expanded from PHHs were fully characterized in vitro. Herein, ProliHHs generated from multiple PHHs donors could be expanded more than 200-fold within four passages and maintained their metabolic or transporter capacities partially. Furthermore, ProliHHs were able to regain the mature hepatic property after three-dimensional (3D) culture. Particularly, the downregulated mRNA expression and function of three major cytochrome P450 (P450) enzymes (CYP1A2, CYP2B6, and CYP3A4) in the proliferating process (ProliHHs-P) could be recovered by 3D culture. The metabolic variabilities across different PHHs donors could be inherited to their matured ProliHHs (ProliHHs-M). The intrinsic clearances of seven major P450 enzymes in ProliHHs-M correlated well (r = 0.87) with those in PHHs. Also, bile canaliculi structures could be observed in sandwich-cultured ProliHHs (SC-ProliHHs), and the biliary excretion index of four probe compounds [cholyl-lys-fluorescein, 5-(and-6)-carboxy-2′, 7′-dichlorofluorescein diacetate (CDF), deuterium-labeled sodium taurocholate acid, and rosuvastatin] in SC-ProliHHs (>10%) were close to sandwich-cultured PHHs. More importantly, both ProliHHs-P and ProliHHs-M could be used to evaluate hepatotoxicity. Therefore, these findings demonstrated that the 3D and sandwich culture system could be used to recover the metabolic and transporter functions in ProliHHs for clearance prediction and cholestasis risk assessment, respectively. Together, ProliHHs could be a promising substitute for PHHs in drug metabolism, transport, and hepatotoxicity screening.Significance StatementThis report describes the study of drug metabolic capacities, efflux transporter functions, and toxicity assessments of proliferating human hepatocytes (ProliHHs). The metabolic variability in different primary human hepatocyte donors could be inherited by their matured ProliHHs derivatives. Also, ProliHHs could form canalicular networks in sandwich culture and display biliary excretion capacities. More importantly, both the proliferative and maturation statuses of ProliHHs could be used to evaluate hepatotoxicity. Together, ProliHHs were feasible to support drug candidate screening in hepatic metabolism, disposition, and toxicity.

C23H25NO9, orthorhombic, P21212 (no. 18), a= 15.8641(6) Å, b= 11.1230(4) Å, c= 13.0925(5) Å, V= 2310.26(15) Å3, Z= 4, Rgt(F) = 0.0372, wRref(F2) = 0.0883, T = 298 K.

C8H8N4O3Zn, tetragonal, P4‾c2$P‾{4}c2$(no. 116), a= 7.340(1) Å, c= 18.285(4) Å, V= 985.1(3) Å3, Z= 4, Rgt(F) = 0.0404, ωRref(F2) = 0.1214, T = 100 K.

A CoII18L6hexameric metal–organic nanocapsule (MONC) has been prepared and characterized using biomimetic self-assembly as the synthetic methodology. Akin to the biological behavior of zinc-finger proteins’ release, uptake, and electrophilic substitution of Zn2+ions, the assembly of this novel MONC has been accomplished by employing three sequential processes: assembly of the framework, metal ion insertion, and metal exchange, resulting in the formation of the CoII18L6hexameric MONC. In this work, inspired by the biological behavior of metalloproteins, rational control of multiple complex supramolecular self-assembly has been achieved.

Here we report the controlled self-assembly of vanadium-seamed metal–organic nanocapsules with specific metal oxidation state distributions. Three supramolecular assemblies composed of the same numbers of components including 24 metal centers and six pyrogallol[4]arene ligands were constructed: a VIII24L6capsule, a mixed-valence VIII18VIV6L6capsule, and a VIV24L6capsule. Crystallographic studies of the new capsules reveal their remarkable structural complexity and geometries, while marked differences in metal oxidation state distribution greatly affect the photoelectric conversion properties of these assemblies. This work therefore represents a significant step forward in the construction of intricate metal–organic architectures with tailored structure and functionality.

C11H13CrN2O9, orthorhombic, Pbca(no. 61), a= 6.7740(14) Å, b= 12.309(3) Å, c= 32.776(7) Å, V= 2732.9(10) Å3, Z= 8, Rgt(F) = 0.0302, wRref(F2) = 0.0867, T= 100(2) K.

The ever-increasing therapeutic and pharmaceutical demand for liver cells calls for systems that enable mass production of hepatic cells. Here we describe a large-scale suspension system that uses human endoderm stem cells (hEnSCs) as precursors to generate functional and transplantable hepatocytes (E-heps) or cholangiocytes (E-chos). hEnSC-derived hepatic populations are characterized by single-cell transcriptomic analyses and compared with hESC-derived counterparts, in-vitro-maintained or -expanded primary hepatocytes and adult cells, which reveals that hepatic differentiation of hEnSCs recapitulates in vivodevelopment and that the heterogeneities of the resultant populations can be manipulated by regulating the EGF and MAPK signaling pathways. Functional assessments demonstrate that E-heps and E-chos possess properties comparable with adult counterparts and that, when transplanted intraperitoneally, encapsulated E-heps were able to rescue rats with acute liver failure. Our study lays the foundation for cell-based therapeutic agents and in vitroapplications for liver diseases.

C4H8CoO8, monoclinic, P21/c(no. 14), a= 5.7952(3) Å, b= 13.0110(7) Å, c= 10.2682(6) Å, β= 98.8320(10)°, V= 765.06(7) Å3, Z= 4, Rgt(F) = 0.0207, ωRref(F2) = 0.0499, T= 301(2) K.

Transplantation of human hepatocytes (HHs) holds significant potential for treating liver diseases. However, the supply of transplantable HHs is severely constrained by limited donor availability and compromised capacity for in vitroexpansion. In response to chronic injury, some HHs are reprogrammed into proliferative cells that express both hepatocyte and progenitor markers, suggesting exploitable strategies for expanding HHs in vitro. Here, we report defined medium conditions that allow 10,000-fold expansion of HHs. These proliferating HHs are bi-phenotypic, partially retaining hepatic features while gaining expression of progenitor-associated genes. Importantly, these cells engraft into injured mouse liver at a level comparable to primary HHs, and they undergo maturation following transplantation in vivoor differentiation in vitro. Thus, this study provides a protocol that enables large-scale expansion of transplantable HHs, which could be further developed for modeling and treating human liver disease.