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G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury. [Display omitted] • GPR56 is a potent ferroptosis suppressor • GPR56 remodels lipid metabolism to defend against ferroptosis via downregulating CD36 • Identification of 17-OH PREG as a potent agonist of GPR56 to inhibit ferroptosis • Targeting the GPR56-17-OH PREG-CD36 axis is beneficial for ferroptosis-induced liver injury Lin et al. found that adhesion GPCR family member GPR56 remodels CD36-mediated lipid metabolism to defend against ferroptosis. They also identified that 17-OH PREG acts as the endogenous agonist of GPR56 to suppress ferroptosis. Targeting the GPR56-17-OH PREG-CD36 axis efficiently alleviated ferroptosis-induced liver injury. [ABSTRACT FROM AUTHOR]

Preclinical studies involving stem cells require efficient physiochemical regulations on the fate of such cells. Because of their unique planar structure, metallic conductivity, and flexible surface functionalization, MXenes show potential for modulating stem cell fate. Here, the Ti 3 C 2 T x MXenenanosheets are dispersed on tissue culture polystyrene (TCPS). When primary mouse neural stem cells (NSCs) are cultured on laminin-coated Ti 3 C 2 T x MXene film, they form stable adhesion, retain their proliferative ability, and show extensive spreading of terminal extensions. With respect to their functional activity, NSCs cultured on Ti 3 C 2 T x MXene films form more active and synchronous network activity than those cultured on TCPS substrates. Moreover, Ti 3 C 2 T x MXene film significantly promotes the neural differentiation and the neurons have longer neurites and greater numbers of branch points and branch tips. NSC-derived neurons grown on the Ti 3 C 2 T x MXene film preserved normal synapse development. Finally, electrical stimulation coupled with Ti 3 C 2 T x MXene film significantly enhances the proliferation of NSCs. These results indicate that Ti 3 C 2 T x MXene is an efficient interface for the proliferation and neural differentiation of NSC and the maturation of NSC-derived neurons, which expands the potential uses of the MXene family of materials and provides new strategies for stem cell studies. The 2DTi 3 C 2 T x MXenenanosheets were applied to be an interface for regulating neural stem cells (NSCs). NSCs cultured on Ti 3 C 2 T x MXene film possessed higher proliferative ability with higher and more synchronous electrical activities. Moreover, Ti 3 C 2 T x MXene film significantly promoted the neural differentiation ratio of NSCs, and the neurons derived from NSCs cultured on Ti 3 C 2 T x MXene film had longer neurites and greater numbers of branch points and branch tips.When electrical stimulation was applied to NSCs via the Ti 3 C 2 T x MXene film, it significantly enhanced the proliferation of NSCs. This work expands the potential uses of the MXene family of materials and provides new strategies for stem cell studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Nerve regeneration based on neural stem cell therapy has become a promising cure for neurological disorders in recent decades. Various kinds of biomaterials have been developed to guide the oriented growth of newborn neurites, which is the fundamental factor to the synaptic connection of newly differentiated neurons with the desired partners during the regeneration. However, the applied biomaterials are usually incapable of guidance with multiple directions, besides, the underlying guiding mechanism has yet to be clearly stated. In this paper, a novel guiding approach based on the magnetic colloidal nanochains was designed for the oriented growth of newborn neurites. The magnetic colloidal nanochains with aligned topography were fabricated from the self-assembly of the magnetic colloidal nanoparticles under the magnetic field. Well orientation of the newborn neurites from the seeded spiral ganglion neurons (SGNs) was found along the nanochains, which induced the alignment of the seeded SGNs. In addition, the growth cone development and synapse formation of the seeded SGNs was promoted under the guidance of the nanochains, which possessed important significance in the rearrangement of nerve network and recovery of neural signal communication during the regeneration. Importantly, the multidirectional nanochains could be constructed by regulating the magnetic field, which contributed to the oriented guidance of SGNs alignment with multiple directions. This feature facilitated to the complex regenerate environment of the nervous system in vitro. Furthermore, the underlying guiding mechanism was revealed by the transcriptome analysis, which showed well consistent with the "contact guidance" of the nanochains. Thus, it was demonstrated that the magnetic colloidal nanochains possessed huge value in biomedical applications. [Display omitted] • magnetic inducing self-assembly nanomaterials. • multidirectional guiding cue of re-growth of axons applied in nerve regeneration. • analysis of the biological effect of the magnetic inducing self-assembly nanomaterials at transcriptomic level. [ABSTRACT FROM AUTHOR]

The mammalian cochlea cannot regenerate functional hair cells (HCs) spontaneously. Atoh1 overexpression as well as other strategies are unable to generate functional HCs. Here, we simultaneously upregulated the expression of Gfi1 , Pou4f3 , and Atoh1 in postnatal cochlear supporting cells (SCs) in vivo , which efficiently converted SCs into HCs. The newly regenerated HCs expressed HC markers Myo7a, Calbindin, Parvalbumin, and Ctbp2 and were innervated by neurites. Importantly, many new HCs expressed the mature and terminal marker Prestin or vesicular glutamate transporter 3 (vGlut3), depending on the subtypes of the source SCs. Finally, our patch-clamp analysis showed that the new HCs in the medial region acquired a large K+ current, fired spikes transiently, and exhibited signature refinement of ribbon synapse functions, in close resemblance to native wild-type inner HCs. We demonstrated that co-upregulating Gfi1 , Pou4f3, and Atoh1 enhances the efficiency of HC generation and promotes the functional maturation of new HCs. [Display omitted] • Gfi1, Pou4f3, and Atoh1 (GPA) enhance the generation of cochlear hair cells (HCs) • GPA-induced HCs express the terminal markers of both the inner and outer HCs • Gfi1 and Pou4f3 promote the functional maturation of Atoh1-induced new hair cells Chen et al. show that overexpression of Gfi1 and Pou4f3 simultaneously with Atoh1 enhances the efficiency of cochlear hair cell generation and promotes the functional maturation of new hair cells, representing a step forward in generating functional hair cells in the mammalian cochlea. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a common lethal injury to the central nervous system (CNS), which severely affects the quality of life of SCI patients. Attempts to enhance the treatment of SCI typically tend to develop functional bioactive hydrogel scaffolds with drug encapsulation. In this work, we proposed novel RGD-functionalized bioactive hydrogel loaded with bone marrow stromal cells-derived exosomes (BMSC-EXOs) and glial cell line-derived neurotrophic factor (GDNF) to synergistically promote SCI repair. The functional hydrogel consisted of methacrylic anhydride-grafted sodium alginate and acrylated RGD, and then combined with BMSC-EXOs and GDNF by photocrosslinking to form a composite bioactive hydrogel. The hydrogel showed good drug-release properties and biocompatibility. When the bioactive hydrogel was implanted into the SCI area of the SD rats, it effectively modulated the adverse inflammatory response in the SCI area. Furthermore, the bioactive hydrogel promoted the regeneration of spinal cord neurons and axons, leading to the improvement in motor function recovery. These results indicate that the bioactive hydrogel loaded with BMSC-EXOs and GDNF has great potential as a therapeutic approach for the repair of spinal cord injuries. • Bioactive hydrogels loaded with BMSC-EXOs and GDNF promotes neural and motor function recovery after spinal cord injury. • RGD-functionalized bioactive hydrogels encapsulated therapeutic bioactive factors. • BMSC-EXOs regulates the inflammatory microenvironment in the injured area. • GDNF enhances neuronal survival and promotes axon regeneration. [ABSTRACT FROM AUTHOR]

Myosin VI is an actin-associated molecular motor vital for auditory and vestibular function. It is encoded by MYO6 located on chromosome 6q13 in human. Pathogenic variants in MYO6 have been associated with both dominant and recessive forms of hearing loss. However, the molecular mechanisms remain unclear. We established a humanized knock-in mouse model, Myo6-C442Y , to mimic the p.C442Y missense variant identified in human patients with autosomal dominant nonsyndromic hearing loss designated as DFNA22. We characterized hearing and inner ear morphologies of Myo6-C442Y and wild-type control mice. We found that both homozygous and heterozygous Myo6 - C442Y mice exhibited hearing loss from three weeks after birth that rapidly progressed to profound deafness by six to nine weeks of age. The hearing loss corresponded to the degeneration of hair cells in the organ of Corti. We also observed disorganized stereocilia with irregular morphological features by immunohistochemistry and scanning electron microscopy. Additionally, hearing loss and inner-ear morphological anomalies were more pronounced and deteriorated more drastically in homozygous than in heterozygous Myo6 - C442Y mice, indicating a semi-dominant inheritance pattern. Heterozygous Myo6 - C442Y mice recapitulated the progressive postlingual sensorineural deafness in human, thus providing a useful model for elucidating the role myosin VI plays in the mammalian auditory system. Furthermore, the late-onset hearing loss of this mouse model may provide a therapeutic window for the emerging gene therapy, a promising strategy to treat certain forms of genetic deafness. • Myo6-C442Y mouse, the humanized knock-in model, firstly mimics the p.C442Y variant of DFNA22. • Myo6-C442Y mouse displays semi-dominant inherited progressive hearing loss. • Cochlear hair cells of Myo6-C442Y mouse degenerate gradually over time. • The hearing trait of this model may provide a therapeutic window for gene therapy. [ABSTRACT FROM AUTHOR]

Highlights • Surgery-free VOR measurement that allows screen for genes and drugs affecting vestibular function has been enabled. • Daily-progression profile of the vestibular impairment caused by IDPN at different dose levels has been obtained. • Mice with homozygous mutations of Lhfpl5 and Cdh23 have been identified based on their reduced VOR-response levels. Abstract Vestibulo-ocular reflex (VOR) responding to acceleration stimuli is originated from the vestibular apparatuses and thus widely used as an in vivo indicator of the vestibular function. We have developed a vestibular function testing (VFT) system that allows to evaluate VOR response with improved efficiency. The previously required surgical procedure has been avoided by using a newly designed animal-immobility setup. The efficacy of our VFT system was demonstrated on the mice with vestibular abnormalities caused by either genetic mutations (Lhfpl5−/− or Cdh23−/−) or applied vestibulotoxicant (3,3′-iminodipropionitrile, IDPN). Daily longitudinal inspection of the VOR response in the IDPN-administered mice gives the first VOR-based daily-progression profile of the vestibular impairment. The capability of VOR in quantifying the severity of toxicant-induced vestibular deficits has been also demonstrated. The acquired VOR-measurement results were validated against the corresponding behavioral-test results. Further validation against immunofluorescence microscopy was applied to the VOR data obtained from the IDPN-administered mice. We conclude that the improved efficiency of our surgery-free VFT system, firstly, enables the characterization of VOR temporal dynamics and quantification of vestibular-impairment severity that may reveal useful information in toxicological and/or pharmaceutical studies; and, secondly, confers our system promising potential to serve as a high-throughput screener for identifying genes and drugs that affect vestibular function. [ABSTRACT FROM AUTHOR]

Abstract The development of therapeutic interventions for hearing loss requires a detailed understanding of the genes and proteins involved in hearing. The FOXG1 protein plays an important role in early neural development and in a variety of neurodevelopmental disorders. Previous studies have shown that there are severe deformities in the inner ear in Foxg1 knockout mice, but due to the postnatal lethality of Foxg1 knockout mice, the role of FOXG1 in hair cell (HC) development and survival during the postnatal period has not been investigated. In this study, we took advantage of transgenic mice that have a specific knockout of Foxg1 in HCs, thus allowing us to explore the role of FOXG1 in postnatal HC development and survival. In the Foxg1 conditional knockout (CKO) HCs, an extra row of HCs appeared in the apical turn of the cochlea and some parts of the middle turn at postnatal day (P)1 and P7; however, these HCs gradually underwent apoptosis, and the HC number was significantly decreased by P21. Auditory brainstem response tests showed that the Foxg1 CKO mice had lost their hearing by P30. The RNA-Seq results and the qPCR verification both showed that the Wnt, Notch, IGF, EGF, and Hippo signaling pathways were down-regulated in the HCs of Foxg1 CKO mice. The significant down-regulation of the Notch signaling pathway might be the reason for the increased numbers of HCs in the cochleae of Foxg1 CKO mice at P1 and P7, while the down-regulation of the Wnt, IGF, and EGF signaling pathways might lead to subsequent HC apoptosis. Together, these results indicate that knockout of Foxg1 induces an extra row of HCs via Notch signaling inhibition and induces subsequent apoptosis of these HCs by inhibiting the Wnt, IGF, and EGF signaling pathways. This study thus provides new evidence for the function and mechanism of FOXG1 in HC development and survival in mice. Highlights • The first study to conditionally knockout FoxG1 in hair cells that avoid the embryonic lethality of FoxG1 systemic knockout mice. • The first study to assess the influence of FoxG1 knockout on hair cells survival in adult mice. • The first study to analyse the molecular mechanism of FoxG1 regulation network in hair cells development and survival. [ABSTRACT FROM AUTHOR]

The damage or degeneration of spiral ganglion neurons (SGNs) can impair the auditory signals transduction from hair cells to the central auditory system, and cause significant hearing loss. Herein, a new form of bioactive hydrogel incorporating topological graphene oxide (GO) and TEMPO-oxidized bacterial cellulose (GO/TOBC hydrogel) was developed to provide a favorable microenvironment for SGN neurite outgrowth. As the network structure of lamellar interspersed fiber cross-linked by GO/TOBC hydrogels well simulated the structure and morphology of ECM, with the controllable hydrophilic property and appropriate Young's modulus well met those requirements of SGNs microenvironment, the GO/TOBC hybrid matrix exhibited great potential to promote the growth of SGNs. The quantitative real-time PCR result confirmed that the GO/TOBC hydrogel can significantly accelerate the development of growth cones and filopodia, by increasing the mRNA expression levels of diap3 , fscn2 , and integrin β1. These results suggest that GO/TOBC hydrogel scaffolds have the potential to be used to construct biomimetic nerve grafts for repairing or replacing nerve defects. [Display omitted] [ABSTRACT FROM AUTHOR]

Accumulated evidence indicates that polymorphisms in human leukocyte antigens (HLA) are associated with susceptibility to coronary artery disease (CAD). However, whether HLA-DQB1 alleles are correlated with susceptibility to CAD is unclear. In this study, significantly lower frequencies of the allele groups (DQB1*03:01:01G and DQB1*05:03:01G) and the genotypes (DQB1*03:01:01G/DQB1*03:01:01G and DQB1*03:01:01G/DQB1*05:03:01G) were observed in the CAD group compared with that in the controls. However, notably higher frequencies of DQB1*04:01:01G and genotype DQB1*05:01:01G/DQB1*03:01:01G were observed in the CAD patients than in the controls. Further analysis in subgroups showed that DQB1*03:01:01G was present at a significantly lower frequency in both female and male CAD patients compared with the corresponding controls; however, DQB1*04:01:01G was overtly high only in male CAD patients. CAD patients with diabetes showed a negative association with DQB1*03:01:01G and DQB1*05:03:01G and a positive association with DQB1*04:01:01G, DQB1*03:02:01G and DQB1*03:03:02G. Results of logistic regression analysis indicated that DQB1*03:01:01G and DQB1*05:03:01G were significantly associated with reduced susceptibility to CAD, but DQB1*04:01:01G, DQB1*03:02:01G and DQB1*03:03:02G had no correlation with CAD. Together, these findings indicate that CAD in Southern Han Chinese is negatively associated with HLA-DQB1*03:01:01G and DQB1*05:03:01G, and males with HLA-DQB1*04:01:01G are likely to have high risk for CAD. [ABSTRACT FROM AUTHOR]

In order to govern cell-specific behaviors in tissue engineering for neural repair and regeneration, a better understanding of material-cell interactions, especially the bioelectric functions, is extremely important. Graphene has been reported to be a potential candidate for use as a scaffold and neural interfacing material. However, the bioelectric evolvement of cell membranes on these conductive graphene substrates remains largely uninvestigated. In this study, we used a neural stem cell (NSC) model to explore the possible changes in membrane bioelectric properties – including resting membrane potentials and action potentials – and cell behaviors on graphene films under both proliferation and differentiation conditions. We used a combination of single-cell electrophysiological recordings and traditional cell biology techniques. Graphene did not affect the basic membrane electrical parameters (capacitance and input resistance), but resting membrane potentials of cells on graphene substrates were more strongly negative under both proliferation and differentiation conditions. Also, NSCs and their progeny on graphene substrates exhibited increased firing of action potentials during development compared to controls. However, graphene only slightly affected the electric characterizations of mature NSC progeny. The modulation of passive and active bioelectric properties on the graphene substrate was accompanied by enhanced NSC differentiation. Furthermore, spine density, synapse proteins expressions and synaptic activity were all increased in graphene group. Modeling of the electric field on conductive graphene substrates suggests that the electric field produced by the electronegative cell membrane is much higher on graphene substrates than that on control, and this might explain the observed changes of bioelectric development by graphene coupling. Our results indicate that graphene is able to accelerate NSC maturation during development, especially with regard to bioelectric evolvement. Our findings provide a fundamental understanding of the role of conductive materials in tuning the membrane bioelectric properties in a graphene model and pave the way for future studies on the development of methods and materials for manipulating membrane properties in a controllable way for NSC-based therapies. [ABSTRACT FROM AUTHOR]

[Display omitted] • 3D-BC/G scaffold was fabricated by in situ BC interfacial polymerization on GF. • It provided supporting for NSC culture and neural network formation. • It enhanced network activities of cortical neurons. • Gene expressions of NSC cultured on 3D-BC/G were studied by RNA-Seq. Neural stem cell (NSC)-based therapy is a promising candidate for treating neurodegenerative diseases and the preclinical researches call an urgent need for regulating the growth and differentiation of such cells. The recognition that three-dimensional culture has the potential to be a biologically significant system has stimulated an extraordinary impetus for scientific researches in tissue engineering and regenerative medicine. Here, A novel scaffold for culturing NSCs, three-dimensional bacterial cellulose-graphene foam (3D-BC/G), which was prepared via in situ bacterial cellulose interfacial polymerization on the skeleton surface of porous graphene foam has been reported. 3D-BC/G not only supports NSC growth and adhesion, but also maintains NSC stemness and enhances their proliferative capacity. Further phenotypic analysis indicated that 3D-BC/G induces NSCs to selectively differentiate into neurons, forming a neural network in a short amount of time. The scaffold has good biocompatibility with primary cortical neurons enhancing the neuronal network activities. To explore the underlying mechanisms, RNA-Seq analysis to identify genes and signaling pathways was performed and it suggests that 3D-BC/G offers a more promising three-dimensional conductive substrate for NSC research and neural tissue engineering, and the repertoire of gene expression serves as a basis for further studies to better understand NSC biology. [ABSTRACT FROM AUTHOR]

With the function of mediating intercellular communication between cells, extracellular vesicles (EVs) have been intently studied for their physiopathology and clinical application values. However, efficient EV isolation from biological fluids remains a significant challenge. To address this, this work constructs a new microvortex chip that can isolate EVs efficiently by integrating the lipid nanoprobe modified Morpho Menelaus (M. Menelaus) butterfly wing into microfluidic chip. M. Menelaus wing is well known for its orderly arranged periodic nanostructures and can generate microvortex when liquid passes through it, leading to increased interaction between EVs and M. Menelaus wing. In addition, the nanoprobe containing lipid tails can be inserted into EVs through their lipid bilayer membrane structure. Based on the described properties, high-throughput enrichment of EVs with over 70% isolation efficiency was realized. Moreover, it was demonstrated that the nanoprobe system based on M. Menelaus wing enabled downstream biological analysis of nucleic acids and proteins in EVs. Microvortex chips showed potential application value in efficient EV isolation for biomedical research and cancer diagnosis. Efficient EV isolation and enrichment by the lipid nanoprobe modifed Morpho wings. The Morpho wings with micro-groove structures were modified with lipid nanoprobes. As the lipid tail of the nanoprobes could insert into EV membranes, EVs could be captured by Morpho wings efficiently. Image 1 • We used butterfly wings to isolate EVs, and integrated wings into microfluidic chips and constructed a new type of microvortex chips for EVs enrichment. • M. Menelaus wings as a natural photonic crystal, can enhance the fluorescence intensity which is benefit for the biological detection. • M. Menelaus wings modified with lipid nanoprobes can achieve high-throughput enrichment of EVs. [ABSTRACT FROM AUTHOR]

• Graphene promotes neuronal differentiation of NSCs. • Enriched and differentially expressed genes are identified on graphene films. • Graphene coupling affects transcriptomic regulation of NSCs. Graphene exhibits excellent mechanical strength, electrical conductivity and good biocompatibility, which make it a suitable candidate as a neural interfacing material in regenerative medicine and tissue engineering. Graphene is reported to promote both of neural stem cells (NSCs) proliferation and differentiation. However, the transcriptomes of 2D graphene-regulated NSC differentiation have not yet been investigated. To identify candidate genes, on which graphene may affect, we used next-generation RNA sequencing to analyze the transcriptome of NSCs differentiated for 21 days on a graphene substrate. These NSCs displayed highly enriched and differentially expressed genes compared with traditional cell culture in vitro. Of these, we identified motor protein genes that might regulate NSC differentiation, including cytoplasmic dynein and axonemal dynein genes, Ccdc108 , Dnah5, and Dnah11. Furthermore, we analyzed the cell signaling pathway genes that might regulate NSC differentiation, and we constructed a protein-protein interaction network for the genes that are differentially expressed in NSCs on graphene compared to commercial tissue culture polystyrene substrates. We have identified genes potentially regulating the differentiation and migration of NSCs on graphene substrates, and our findings provide mechanistic evidence for the biological activities of graphene, especially in view of graphene-stem cell interactions. [ABSTRACT FROM AUTHOR]