On the cell biology of pit cells,the liver-specific NK cells

INTRODUCTION Natural killer (NK) cells are functionally defined by their ability to kill certain tumor cells and virus-infected cells without prior

Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology

Brain-derived neurotrophic factor（BDNF） plays an important role in neurodevelopment,synaptic plasticity,learning and memory,and in preventing neurodegeneration.Despite decades of investigations into downstream signaling cascades and changes in cellular processes,the mechanisms of how BDNF reshapes circuits in vivo remain unclear.This informational gap partly arises from the fact that the bulk of studies into the molecular actions of BDNF have been performed in dissociated neuronal cultures,while the majority of studies on synaptic plasticity,learning and memory were performed in acute brain slices or in vivo.A recent study by Bowling-Bhattacharya et al.,measured the proteomic changes in acute adult hippocampal slices following treatment and reported changes in proteins of neuronal and non-neuronal origin that may in concert modulate synaptic release and secretion in the slice.In this paper,we place these findings into the context of existing literature and discuss how they impact our understanding of how BDNF can reshape the brain.

Central nervous system tumors and three-dimensional cell biology: Current and future perspectives in modeling

Central nervous system(CNS)tumors are a variety of distinct neoplasms that present multiple challenges in terms of treatment and prognosis.Glioblastoma,the most common primary tumor in adults,is associated with poor survival and remains one of the least treatable neoplasms.These tumors are highly heterogenous and complex in their nature.Due to this complexity,traditional cell culturing techniques and methods do not provide an ideal recapitulating model for the study of these tumors’behavior in vivo.Two-dimensional models lack the spatial arrangement,the heterogeneity in cell types,and the microenvironment that play a large role in tumor cell behavior and response to treatment.Recently,scientists have turned towards three-dimensional culturing methods,namely spheroids and organoids,as they have been shown to recapitulate tumors in a more faithful manner to their in vivo counterparts.Moreover,tumor-on-a-chip systems have lately been employed in CNS tumor modeling and have shown great potential in both studying the pathophysiology and therapeutic testing.In this review,we will discuss the current available literature on in vitro threedimensional culturing models in CNS tumors,in addition to presenting their advantages and current limitations.We will also elaborate on the future implications of these models and their benefit in the clinical setting.

Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.

Skin appendage-derived stem cells: cell biology and potential for wound repair

Stem cells residing in the epidermis and skin appendages are imperative for skin homeostasis and regeneration.These stem cells also participate in the repair of the epidermis after injuries,inducing restoration of tissue integrity and function of damaged tissue.Unlike epidermis-derived stem cells,comprehensive knowledge about skin appendage-derived stem cells remains limited.In this review,we summarize the current knowledge of skin appendage-derived stem cells,including their fundamental characteristics,their preferentially expressed biomarkers,and their potential contribution involved in wound repair.Finally,we will also discuss current strategies,future applications,and limitations of these stem cells,attempting to provide some perspectives on optimizing the available therapy in cutaneous repair and regeneration.

Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.

The mini player with diverse functions:extracellular vesicles in cell biology,disease,and therapeutics

Extracellular vesicles(EVs)are tiny biological nanovesicles ranging from approximately 30–1000 nm in diameter that are released into the extracellular matrix of most cell types and in biofluids.The classification of EVs includes exosomes,microvesicles,and apoptotic bodies,dependent on various factors such as size,markers,and biogenesis pathways.The transition of EV relevance from that of being assumed as a trash bag to be a key player in critical physiological and pathological conditions has been revolutionary in many ways.EVs have been recently revealed to play a crucial role in stem cell biology and cancer progression via intercellular communication,contributing to organ development and the progression of cancer.This review focuses on the significant research progress made so far in the role of the crosstalk between EVs and stem cells and their niche,and cellular communication among different germ layers in developmental biology.In addition,it discusses the role of EVs in cancer progression and their application as therapeutic agents or drug delivery vehicles.All such discoveries have been facilitated by tremendous technological advancements in EV-associated research,especially the microfluidics systems.Their pros and cons in the context of characterization of EVs are also extensively discussed in this review.This review also deliberates the role of EVs in normal cell processes and disease conditions,and their application as a diagnostic and therapeutic tool.Finally,we propose future perspectives for EV-related research in stem cell and cancer biology.

Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.

Insights into female germ cell biology： from in vivo development to in vitro derivations

Understanding the mechanisms of human germ cell biology is important for developing infertility treatments. However, little is known about the mechanisms that regulate human gametogenesis due to the difficulties in collecting samples, especially germ cells during fetal development. In contrast to the mitotic arrest of spermatogonia stem cells in the fetal testis, female germ cells proceed into meiosis and began folliculogenesis in fetal ovaries. Regulations of these developmental events, including the initiation of meiosis and the endowment of primordial follicles, remain an enigma. Studying the molecular mechanisms of female germ cell biology in the human ovary has been mostly limited to spatiotemporal characterizations of genes or proteins. Recent efforts in utilizing in vitro differentiation system of stem cells to derive germ cells have allowed researchers to begin studying molecular mechanisms during human germ cell development. Meanwhile, the possibility of isolating female germline stem cells in adult ovaries also excites researchers and generates many debates. This review will mainly focus on presenting and discussing recent in vivo and in vitro studies on female germ cell biology in human. The topics will highlight the progress made in understanding the three main stages of germ cell developments： namely, primordial germ cell formation, meiotic initiation, and folliculogenesis.

Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy:A case report and review of literature

BACKGROUND Hepatocellular carcinoma(HCC)is one of the leading causes of death due to its complexity,heterogeneity,rapid metastasis and easy recurrence after surgical resection.We demonstrated that combination therapy with transcatheter arterial chemoembolization(TACE),hepatic arterial infusion chemotherapy(HAIC),Epclusa,Lenvatinib and Sintilimab is useful for patients with advanced HCC.CASE SUMMARY A 69-year-old man who was infected with hepatitis C virus(HCV)30 years previously was admitted to the hospital with abdominal pain.Enhanced computed tomography(CT)revealed a low-density mass in the right lobe of the liver,with a volume of 12.9 cm×9.4 cm×15 cm,and the mass exhibited a“fast-in/fast-out”pattern,with extensive filling defect areas in the right branch of the portal vein and an alpha-fetoprotein level as high as 657 ng/mL.Therefore,he was judged to have advanced HCC.During treatment,the patient received three months of Epclusa,three TACE treatments,two HAIC treatments,three courses of sintilimab,and twenty-one months of lenvatinib.In the third month of treatment,the patient developed severe side effects and had to stop immunotherapy,and the Lenvatinib dose had to be halved.Postoperative pathological diagnosis indicated a complete response.The patient recovered well after the operation,and no tumor recurrence was found.CONCLUSION Multidisciplinary conversion therapy for advanced enormous HCC caused by HCV infection has a significant effect.Individualized drug adjustments should be made during any treatment according to the patient's tolerance to treatment.

A year of change for Journal of Molecular Cell Biology

In recent years,the scientific publishing world has been significantly changed from focusing on impact factor to encouraging scientific merit and from subscriptional access to open access(Wu,2018).Journal of Molecular Cell Biology(JMCB), which was launched in October 2009,started a new journey following the new routes in the scientific publishing world from the beginning of 2019.Here,I would like to go through what JMCB has fulfilled in the first year of change.

The MORC2 p.S87L mutation reduces proliferation of pluripotent stem cells derived from a patient with the spinal muscular atrophy-like phenotype by inhibiting proliferation-related signaling pathways

Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical phenotype.The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies.Epithelial cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor cells.Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells.Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient.MORC2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem cells.Howeve r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor cells.These findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction.

Use of induced pluripotent stem cell-derived brain cells,organoids,assembloids,and blood-brain barrier models in understanding alcohol and anesthetic-induced brain injuries:an emerging perspective

Neurological disorders,including developmental disorders,Alzheimer’s disease(AD),and psychiatric conditions,have significant social and economic impacts globally.Despite extensive research into the underlying mechanisms of these disorders,effective treatments remain elusive,partly due to the complexity of the brain,the limited availability of human brain tissue,and the blood-brain barrier(BBB)’s impermeability to certain drugs.This perspective article discusses the potential of human induced pluripotent stem cell(iPSC)-based models of brain cells,organoids,assembloids,and BBB to advance our understanding of the etiology,progression,and mechanisms of brain injuries induced by alcohol consumption and general anesthesia.These models could also be used to develop protective and therapeutic approaches.

A perspective on age-related changes in cell environment and risk of neurodegenerative diseases

“Age-related neurodegenerative disease”underscores human age as the primary risk factor for disease development:Alzheimer’s,Parkinson’s,and Huntington’s disease(HD)as examples.Reasons for the age-dependent delay in disease manifestation,in particular for autosomal dominant forms of the disease,and the underlying cause(s)of specific neuron dysfunction and death to manifest as memory loss,anxiety,depression,and agitation in disease subjects remain unclear.We are interested in understanding age-related changes in cell environment that can modulate the structure,function,aggregation.

Epigenetic memory of drug exposure history controls neural stem cell quiescence in the adult brain

Neural stem cells(NSCs)are the source of all neurons and glial cells(astrocytes and oligodendrocytes)in the central nervous system.The adult mammalian brain retains NSCs in the subgranular zone of the dentate gyrus in the hippocampus and ventricular subventricular zone lining the lateral ventricle(Olpe and Jessberger,2022).Adult NSCs in rodents are preserved throughout life and continuously produce new neurons that integrate into the pre-existing neuronal network.

Unraveling the nexus between cellular senescence and malignant transformation:a paradigm shift in cancer research

Cellular senescence, a natural process wherein cells cease division and undergo irreversible growth arrest, has long captivated the curiosity of scientists because of its many implications in aging and disease. Recent research has shed light on the nexus between cellular senescence and malignant transformation, thus leading to a paradigm shift in understanding cancer development and progression.

Recent progress in hair follicle stem cell markers and their regulatory roles

Hair follicle stem cells(HFSCs)in the bulge are a multipotent adult stem cell population.They can periodically give rise to new HFs and even regenerate the epidermis and sebaceous glands during wound healing.An increasing number of biomarkers have been used to isolate,label,and trace HFSCs in recent years.Considering more detailed data from single-cell transcriptomics technology,we mainly focus on the important HFSC molecular markers and their regulatory roles in this review.

MAD2L2 overexpression attenuates the effects of TNF-α-induced migration and invasion capabilities in colorectal cancer cells

Background:Colorectal cancer is a major global health concern,exacerbated by tumor necrosis factor-alpha(TNF-α)and its role in inflammation,with the effects of Mitotic Arrest Deficient 2 Like 2(MAD2L2)in this context still unclear.Methods:The colorectal carcinoma cell lines HCT116 and SW620 were exposed to TNF-αfor a period of 24 h to instigate an inflammatory response.Subsequent assessments were conducted to measure the expression of inflammatory cytokines,the activity within the p38 mitogen-activated protein kinase(p38 MAPK)and Phosphoinositide 3-Kinase/AKT Serine/Threonine Kinase pathway(PI3K/AKT)signaling cascades.Transcriptome sequencing and subsequent integrative analysis with the Cancer Genome Atlas(TCGA)program database revealed a significant downregulation of the key factor MAD2L2.Enhancement of MAD2L2 expression was facilitated via lentiviral vector-mediated transfection.The influence of this overexpression on TNF-α-prompted inflammation,intracellular signaling pathways,and the migratory and invasive behaviors of the colorectal cancer cells was then scrutinized.Results:TNF-αtreatment significantly increased the expression of Interleukin-1 beta(IL-1β)and Interleukin-6(IL-6),activated the MAPK p38 and PI3K/AKT signaling pathways,and enhanced cell migration and invasion.A decrease in MAD2L2 expression was observed following TNF-αtreatment.However,overexpression of MAD2L2 reversed the effects of TNF-α,reducing IL-1βand IL-6 levels,attenuating PI3K/AKT pathway activation,and inhibiting cell migration and invasion.Conclusions:Overexpression of MAD2L2 attenuates the pro-inflammatory effects of TNF-α,suggesting that MAD2L2 plays a protective role against TNF-α-induced migration and invasion of colorectal carcinoma cells.Therefore,MAD2L2 holds potential as a therapeutic target in the treatment of colorectal cancer.

Advancements in personalized stem cell models for aging-related neurodegenerative disorders

Neurodegenerative diseases(NDDs)are a class of disorders characterized by the gradual loss or malfunction of specific cell populations in the nervous system,which can be triggered by genetic or environmental factors.As a result,patients often experience a decline in mobility,sensation,memory,and cognition,which can ultimately lead to a fatal outcome.The global incidence of NDDs,including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis(ALS),and multiple sclerosis,is increasing.

SOX11 as a potential prognostic biomarker in hepatocellular carcinoma linked to immune infiltration and ferroptosis

Objective:SOX11 is expressed in numerous malignancies,including hepatocellular carcinomas(HCC),but its oncogenic function has not been elucidated.Here,we performed a comprehensive bioinformatics analysis of the Liver Hepatocellular Carcinoma(LIHC)dataset to investigate the function of SOX11 in tumorgenesis.Methods:SOX11 expression data from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)were validated by immunohistochemistry(IHC).Co-expression,differential expression,and functional analyses utilized TCGA-LIHC,Timer 2.0,Metascape,GTEx,and LinkedOmics databases.Associations with immune infiltration,ferroptosis,and immune checkpoint genes were assessed.Genetic changes were explored via CBioPortal.Logistic regression,receiver operating characteristic curve(ROC),Kaplan-Meier analysis,and nomogram modeling evaluated associations with HCC clinicopathological features.SOX11’s impact on proliferation and migration was studied in HepG2 and HuH7 cell lines.Results:SOX11 was significantly elevated in HCC tumors compared to controls.SOX11-associated genes exhibited differential expression in pathways involving extracellular membrane ion channels.Significant associations were found between SOX11 levels,immune infiltration,ferroptosis,and immune checkpoint genes in HCC tissue.SOX11 levels correlated with HCC stage,histologic grade,and tumor status,and independently predicted overall and disease-specific survival.SOX11 expression effectively distinguished between tumor and normal liver tissue.Spearman correlations highlighted a significant relationship between SOX11 and ferroptosis-associated genes.Decreased SOX11 levels in HepG2 and HuH7 cells resulted in reduced proliferation and migration.Conclusions:SOX11 was found to represent a promising biomarker within HCC diagnosis and prognosis together with being a possible drug-target.