Regulation Of Cell Differentiation Research Articles

Clinical significance of exosomal noncoding RNAs in hepatocellular carcinoma: a narrative review.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, with poor prognosis owing to its high frequency of recurrence and metastasis. Moreover, most patients are diagnosed at an advanced stage owing to a lack of early detection markers. Exosomes, which are characterized by their cargos of stable intracellular messengers, such as DNA, RNA, proteins, and lipids, play a crucial role in regulating cell differentiation and HCC development. Recently, exosomal noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, have become increasingly important diagnostic, prognostic, and predictive markers of HCC. Herein, we discuss the clinical implications of exosomal ncRNAs, specifically those within the HCC regulatory network.

Association of peripheral B cells and delirium: combined single-cell sequencing and Mendelian randomization analysis.

Delirium seriously affects the prognosis of patients and greatly reduces the ability to work and live. Peripheral inflammatory events may contribute to the development of delirium, the mechanism of which is still unclear. There is a lack of effective diagnostic and treatments for delirium in clinical practice. The study aims to investigate alterations in peripheral immune cell subsets under inflammatory stress and to explore causal associations with delirium. Single-cell transcriptional sequencing data of human peripheral blood mononuclear cells (PBMC) before and after lipopolysaccharide (LPS) intervention were processed by the Seurat package in R software. PBMC subsets and cellular markers were defined after downscaling and clustering by the Harmony algorithm to identify characteristic subsets in the context of inflammatory stress. Subsequently, a two-sample Mendelian randomization (MR) study was used to explore the causal associations of these inflammation-related PBMC subsets and their molecular phenotypes with delirium. Based on publicly available genetic data, the study incorporated 70 PBMC-associated immune traits, including 8 types of circulating immune cells, 33 B cell subsets and molecular phenotypes, 13 T cell subsets, and 16 B cell-associated cytokines. The results were also validated for robustness, heterogeneity, and horizontal pleiotropy. Under LPS-induced inflammatory stress, B cells, T cells, monocytes, and dendritic cells in human PBMC showed significant activation and quantitative changes. Of these, only lymphocyte and B cell counts were causally associated with delirium risk. This risk link is also seen in the TNF pathway. Further studies of B cells and their subsets revealed that this association may be related to unswitched memory B cells and CD27 expressed on memory B cells. Annotation of the screened SNPs revealed significant polymorphisms in CD27 and CD40 annotated by rs25680 and rs9883798, respectively. The functions of the key annotated genes may be related to the regulation of immune responses, cell differentiation, proliferation, and intercellular interactions. The present study revealed the potential possibility that B cell, memory B cell subset, and TNF-related molecules may be involved in the development of delirium due to peripheral inflammation, which can provide clues for further investigation of delirium prevention and treatment strategies.

Integrated analysis of differentially expressed genes and miRNA expression profiles in dilated cardiomyopathy

BackgroundAlthough dilated cardiomyopathy (DCM) is a prevalent form of cardiomyopathy, the molecular mechanisms underlying its pathogenesis and progression remain poorly understood. It is possible to identify and validate DCM-associated genes, pathways, and miRNAs using bioinformatics analysis coupled with clinical validation methods. MethodsOur analysis was performed using 3 mRNA datasets and 1 miRNA database. We employed several approaches, including gene ontology (GO) analysis, KEGG pathway enrichment analysis, protein-protein interaction networks analysis, and analysis of hub genes to identify critical genes and pathways linked to DCM. We constructed a regulatory network for DCM that involves interactions between miRNAs and mRNAs. We also validated the differently expressed miRNAs in clinical samples (87 DCM ，83 Normal) using qRT-PCR.The miRNAs' clinical value was evaluated by receiver operating characteristic curves (ROCs). Results78 differentially expressed genes (DEGs) and 170 differentially expressed miRNAs (DEMs) were associated with DCM. The top five GO annotations were collagen-containing extracellular matrix, cell substrate adhesion, negative regulation of cell differentiation, and inflammatory response. The most enriched KEGG pathways were the Neurotrophin signaling pathway, Thyroid hormone signaling pathway, Wnt signaling pathway, and Axon guidance. In the PPI network, we identified 10 hub genes, and in the miRNA-mRNA regulatory network, we identified 8 hub genes and 15 miRNAs. In the clinical validation, we found 13 miRNAs with an AUC value greater than 0.9. ConclusionOur research offers novel insights into the underlying mechanisms of DCM and has implications for identifying potential targets for diagnosis and treatment of this condition.

Age-dependent genes in adipose stem and precursor cells affect regulation of fat cell differentiation and link aging to obesity via cellular and genetic interactions

BackgroundAge and obesity are dominant risk factors for several common cardiometabolic disorders, and both are known to impair adipose tissue function. However, the underlying cellular and genetic factors linking aging and obesity on adipose tissue function have remained elusive. Adipose stem and precursor cells (ASPCs) are an understudied, yet crucial adipose cell type due to their deterministic adipocyte differentiation potential, which impacts the capacity to store fat in a metabolically healthy manner.MethodsWe integrated subcutaneous adipose tissue (SAT) bulk (n=435) and large single-nucleus RNA sequencing (n=105) data with the UK Biobank (UKB) (n=391,701) data to study age-obesity interactions originating from ASPCs by performing cell-type decomposition, differential expression testing, cell-cell communication analyses, and construction of polygenic risk scores for body mass index (BMI).ResultsWe found that the SAT ASPC proportions significantly decrease with age in an obesity-dependent way consistently in two independent cohorts, both showing that the age dependency of ASPC proportions is abolished by obesity. We further identified 76 genes (72 SAT ASPC marker genes and 4 transcription factors regulating ASPC marker genes) that are differentially expressed by age in SAT and functionally enriched for developmental processes and adipocyte differentiation (i.e., adipogenesis). The 76 age-perturbed ASPC genes include multiple negative regulators of adipogenesis, such as RORA, SMAD3, TWIST2, and ZNF521, form tight clusters of longitudinally co-expressed genes during human adipogenesis, and show age-based differences in cellular interactions between ASPCs and adipose cell types. Finally, our genetic data demonstrate that cis-regional variants of these genes interact with age as predictors of BMI in an obesity-dependent way in the large UKB, while no such gene-age interaction on BMI is observed with non-age-dependent ASPC marker genes, thus independently confirming our cellular ASPC results at the biobank level.ConclusionsOverall, we discover that obesity prematurely induces a decrease in ASPC proportions and identify 76 developmentally important ASPC genes that implicate altered negative regulation of fat cell differentiation as a mechanism for aging and directly link aging to obesity via significant cellular and genetic interactions.

Blocking LBH expression causes replication stress and sensitizes triple-negative breast cancer cells to ATR inhibitor treatment.

Triple-negative (ER-PR-HER2-) breast cancers (TNBC) are highly aggressive and difficult to treat. TNBC exhibit high genomic instability, which enables them to adapt and become resistant to chemo/radiation therapy, leading to rapid disease relapse and mortality. The pro-survival factors that safeguard genome integrity in TNBC cells are poorly understood. LBH is an essential mammary stem cell-specific transcription regulator in the WNT pathway that is aberrantly overexpressed in TNBC, correlating with poor prognosis. Herein, we demonstrate a novel role for LBH in promoting TNBC cell survival. Depletion of LBH in multiple TNBC cell models triggered apoptotic cell death both in vitro and in vivo and led to S-G2M cell cycle delays. Mechanistically, LBH loss causes replication stress due to DNA replication fork stalling, leading to ssDNA breaks, ɣH2AX and 53BP1 nuclear foci formation, and activation of the ATR/CHK1 DNA damage response. Notably, ATR inhibition in combination with LBH downmodulation had a synergistic effect, boosting TNBC cell killing and blocking in vivo tumor growth. Our findings demonstrate, for the first time, that LBH protects the genome integrity of cancer cells by preventing replicative stress. Importantly, they uncover new synthetic lethal vulnerabilities in TNBC that could be exploited for future multi-modal precision medicine.

Regulation of spermatogonial stem cell differentiation by Sertoli cells-derived exosomes through paracrine and autocrine signaling.

In the orchestrated environment of the testicular niche, the equilibrium between self-renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously maintained, ensuring a stable stem cell reserve and robust spermatogenesis. Within this milieu, extracellular vesicles, specifically exosomes, have emerged as critical conveyors of intercellular communication. Despite their recognized significance, the implications of testicular exosomes in modulating SSC fate remain incompletely characterized. Given the fundamental support and regulatory influence of Sertoli cells (SCs) on SSCs, we were compelled to explore the role of SC-derived exosomes (SC-EXOs) in the SSC-testicular niche. Our investigation hinged on the hypothesis that SC-EXOs, secreted by SCs from the testes of 5-day-old mice-a developmental juncture marking the onset of SSC differentiation-participate in the regulation of this process. We discovered that exposure to SC-EXOs resulted in an upsurge of PLZF, MVH, and STRA8 expression in SSC cultures, concomitant with a diminution of ID4 and GFRA1 levels. Intriguingly, obstructing exosomal communication in a SC-SSC coculture system with the exosome inhibitor GW4869 attenuated SSC differentiation, suggesting that SC-EXOs may modulate this process via paracrine signaling. Further scrutiny revealed the presence of miR-493-5p within SC-EXOs, which suppresses Gdnf mRNA in SCs to indirectly restrain SSC differentiation through the modulation of GDNF expression-an indication of autocrine regulation. Collectively, our findings illuminate the complex regulatory schema by which SC-EXOs affect SSC differentiation, offering novel perspectives and laying the groundwork for future preclinical and clinical investigations.

In Silico and In Vitro Mapping of Receptor-Type Protein Tyrosine Phosphatase Receptor Type D in Health and Disease: Implications for Asprosin Signalling in Endometrial Cancer and Neuroblastoma

Background: Protein Tyrosine Phosphatase Receptor Type D (PTPRD) is involved in the regulation of cell growth, differentiation, and oncogenic transformation, as well as in brain development. PTPRD also mediates the effects of asprosin, which is a glucogenic hormone/adipokine derived following the cleavage of the C-terminal of fibrillin 1. Since the asprosin circulating levels are elevated in certain cancers, research is now focused on the potential role of this adipokine and its receptors in cancer. As such, in this study, we investigated the expression of PTPRD in endometrial cancer (EC) and the placenta, as well as in glioblastoma (GBM). Methods: An array of in silico tools, in vitro models, tissue microarrays (TMAs), and liquid biopsies were employed to determine the gene and protein expression of PTPRD in healthy tissues/organs and in patients with EC and GBM. Results: PTPRD exhibits high expression in the occipital lobe, parietal lobe, globus pallidus, ventral thalamus, and white matter, whereas in the human placenta, it is primarily localised around the tertiary villi. PTPRD is significantly upregulated at the mRNA and protein levels in patients with EC and GBM compared to healthy controls. In patients with EC, PTPRD is significantly downregulated with obesity, whilst it is also expressed in the peripheral leukocytes. The EC TMAs revealed abundant PTPRD expression in both low- and high-grade tumours. Asprosin treatment upregulated the expression of PTPRD only in syncytialised placental cells. Conclusions: Our data indicate that PTPRD may have potential as a biomarker for malignancies such as EC and GBM, further implicating asprosin as a potential metabolic regulator in these cancers. Future studies are needed to explore the potential molecular mechanisms/signalling pathways that link PTPRD and asprosin in cancer.

Advancements in the Research of GEF-H1: Biological Functions and Tumor Associations.

Guanine nucleotide exchange factor H1 (GEF-H1) is a unique protein modulated by the GDP/GTP exchange. As a regulator of the Rho-GTPase family, GEF-H1 can be activated through a microtubule-depended mechanism and phosphorylation regulation, enabling it to perform various pivotal biological functions across multiple cellular activities. These include the regulation of Rho-GTPase, cytoskeleton formation, cellular barrier, cell cycle, mitosis, cell differentiation, and vesicle trafficking. Recent studies have revealed its crucial effect on the tumor microenvironment (TME) components, promoting tumor initiation and progress. Consequently, an in-depth exploration of GEF-H1's biological roles and association with tumors holds promise for its potential as a valuable molecular target in tumor treatment.

The miR-146b-3p/TNFAIP2 axis regulates cell differentiation in acute myeloid leukaemia.

Our purpose is to verify that miR-146b-3p targets the downstream transcript TNFAIP2 in order to reveal the machinery underlying the miR-146b-3p/TNFAIP2 axis regulating acute myeloid leukaemia (AML) differentiation. Bioinformatics analyses were performed using multiple databases and R packages. The CD11b+ and CD14+ cell frequencies were detected using flow cytometry and immunofluorescence staining. The TNFAIP2 protein expression was evaluated using western blotting, immunocytochemistry and immunofluorescence staining. The qRT-PCR was conducted to detect the expression of TNFAIP2 and miR-146b-3p. TNFAIP2 and its correlated genes were enriched in multiple cell differentiation pathways. TNFAIP2 was upregulated upon leukaemic cell differentiation. miR-146b-3p directly targeted TNFAIP2, resulting in a decrease in TNFAIP2 expression. Forced expression of TNFAIP2 or knockdown of miR-146b-3p significantly induced the differentiation of MOLM-13 cells. In this study, we demonstrated that TNFAIP2 is a critical driver in inducing differentiation and that the miR-146b-3p/TNFAIP2 axis involves in regulating cell differentiation in AML.

Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells

BackgroundBlood homeostasis requires the daily production of millions of terminally differentiated effector cells that all originate from hematopoietic stem cells (HSCs). HSCs are rare and exhibit unique self-renewal and multipotent properties, which depend on their ability to maintain quiescence through ill-defined processes. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignancy. In particular, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Previous studies have identified chromatin coordination as a key regulator of differentiation in embryonic stem cells.ResultsHere, we utilized genetic inactivation of the chromatin-associated Sin3B protein to manipulate cell cycle control and found dysregulated chromatin accessibility and cell cycle progression in HSCs. Single cell transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) inactivated for Sin3B reveals aberrant progression through the G1 phase of the cell cycle, which correlates with the engagement of specific signaling pathways, including aberrant expression of cell adhesion molecules and the interferon signaling program in LT-HSCs. In addition, we uncover the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, which points to cell cycle progression possibly dictating the priming of HSCs for differentiation.ConclusionsOur findings provide new insights into controlled cell cycle progression as a potential regulator of HSC lineage commitment through the modulation of chromatin features.

Rheb1 is required for limb growth through regulating chondrogenesis in growth plate

Ras homology enriched in the brain (Rheb) is well established as a critical regulator of cell proliferation and differentiation in response to growth factors and nutrients. However, the role of Rheb1 in limb development remains unknown. Here, we found that Rheb1 was dynamically expressed during the proliferation and differentiation of chondrocytes in the growth plate. Given that Prrx1+ limb-bud-like mesenchymal cells are the source of limb chondrocytes and are essential for endochondral ossification, we conditionally deleted Rheb1 using Prrx1-Cre and found a limb dwarfism in Prrx1-Cre; Rheb1fl/fl mice. Normalized to growth plate height, the conditional knockout (cKO) mice exhibited a significant decrease in column count of proliferative zones which was increased in hypertrophic zones resulting in decreased growth plate size, indicating abnormal endochondral ossification. Interestingly, although Rheb1 deletion profoundly inhibited the transcription factor Sox9 in limb cartilage; levels of runx2 and collagen type 2 were both increased. These novel findings highlight the essential role of Rheb1 in limb growth and indicate a complex regulation of Rheb1 in chondrocyte proliferation and differentiation.

Transcriptome Analysis of Key Genes Involved in the Initiation of Spermatogonial Stem Cell Differentiation.

The purpose of this study was to screen the genes and pathways that are involved in spermatogonia stem cell (SSC) differentiation regulation during the transition from Aundiff to A1. Methods: RNA sequencing was performed to screen differentially expressed genes at 1 d and 2 d after SSC differentiation culture. KEGG pathway enrichment and GO function analysis were performed to reveal the genes and pathways related to the initiation of early SSC differentiation. The GO analysis showed that Rpl21, which regulates cell differentiation initiation, significantly increased after 1 day of SSC differentiation. The expressions of Fn1, Cd9, Fgf2, Itgb1, Epha2, Ctgf, Cttn, Timp2 and Fgfr1, which are related to promoting differentiation, were up-regulated after 2 days of SSC differentiation. The analysis of the KEGG pathway revealed that RNA transport is the most enriched pathway 1 day after SSC differentiation. Hspa2, which promotes the differentiation of male reproductive cells, and Cdkn2a, which participates in the cell cycle, were significantly up-regulated. The p53 pathway and MAPK pathway were the most enriched pathways 2 days after SSC differentiation. Cdkn1a, Hmga2, Thbs1 and Cdkn2a, microRNAs that promote cell differentiation, were also significantly up-regulated. RNA transport, the MAPK pathway and the p53 pathway may play vital roles in early SSC differentiation, and Rpl21, Fn1, Cd9, Fgf2, Itgb1, Epha2, Ctgf, Cttn, Timp2, Fgfr1, Hspa2, Cdkn2a, Cdkn1a, Hmga2 and Thbs1 are involved in the initiation of SSC differentiation. The findings of this study provide a reference for further revelations of the regulatory mechanism of SSC differentiation.

MRAS in coronary artery disease-Unchartered territory.

Genome-wide association studies (GWAS) have identified coronary artery disease (CAD) susceptibility locus on chromosome 3q22.3. This locus contains a cluster of several genes that includes muscle rat sarcoma virus (MRAS). Common MRAS variants are also associated with CAD causing risk factors such as hypertension, dyslipidemia, obesity, and type II diabetes. The MRAS gene is an oncogene that encodes a membrane-bound small GTPase. It is involved in a variety of signaling pathways, regulating cell differentiation and cell survival (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase) as well as acute phase response signaling (tumor necrosis factor [TNF] and interleukin 6 [IL6] signaling). In this review, we will summarize the role of genetic MRAS variants in the etiology of CAD and its comorbidities with the focus on tissue distribution of MRAS isoforms, cell type/tissue specificity, and mode of action of single nucleotide variants in MRAS associated complex traits. Finally, we postulate that CAD risk variants in the MRAS locus are specific to smooth muscle cells and lead to higher levels of MRAS, particularly in arterial and cardiac tissue, resulting in MAPK-dependent tissue hypertrophy or hyperplasia.

Genetic Analysis of Candida albicans Filamentation by the Iron Chelator BPS Reveals a Role for a Conserved Kinase-WD40 Protein Pair.

Candida albicans is a major human pathogenic fungus that is distinguished by its capability to switch from a yeast to a hyphal morphology under different conditions. Here, we analyze the cellular effects of high concentrations of the iron chelator bathophenanthroline disulfonate (BPS). BPS inhibits cellular growth by withholding iron, but when iron chelation is overcome by the addition of hemoglobin as an iron source, the cells resume growth as hyphae. The BPS hyphal induction pathway was characterized by identifying the hyphal-specific transcription factors that it requires and by a forward genetic screen for mutants that fail to form hyphae in BPS using a transposon library generated in a haploid strain. Among the mutants identified are the DYRK1-like kinase Yak1 and Orf19.384, a homolog of the DYRK1-associated protein WDR68/DCAF7. Orf19.384 nuclear localization depends on Yak1, similar to their mammalian counterparts. We identified the hyphal suppressor transcription factor Sfl1 as a candidate target of Yak1-Orf19.384 and show that Sfl1 modification is similarly affected in the yak1 and orf19.384 mutant strains. These results suggest that DYRK1/Yak1 and WDR68/Orf19.384 represent a conserved protein pair that regulates cell differentiation from fungi to animals.

Molecular Signature of Monocytes Shaped by the Shigella sonnei 1790-Generalized Modules for Membrane Antigens Vaccine.

Shigellosis, an acute gastroenteritis infection caused by Shigella species, remains a public health burden in developing countries. Recently, many outbreaks due to Shigella sonnei multidrug-resistant strains have been reported in high-income countries, and the lack of an effective vaccine represents a major hurdle to counteract this bacterial pathogen. Vaccine candidates against Shigella sonnei are under clinical development, including a Generalized Modules for Membrane Antigens (GMMA)-based vaccine. The mechanisms by which GMMA-based vaccines interact and activate human immune cells remain elusive. Our previous study provided the first evidence that both adaptive and innate immune cells are targeted and functionally shaped by the GMMA-based vaccine. Here, flow cytometry and confocal microscopy analysis allowed us to identify monocytes as the main target population interacting with the S. sonnei 1790-GMMA vaccine on human peripheral blood. In addition, transcriptomic analysis of this cell population revealed a molecular signature induced by 1790-GMMA mostly correlated with the inflammatory response and cytokine-induced processes. This also impacts the expression of genes associated with macrophages' differentiation and T cell regulation, suggesting a dual function for this vaccine platform both as an antigen carrier and as a regulator of immune cell activation and differentiation.

The WOX Genes from the Intermediate Clade: Influence on the Somatic Embryogenesis in Medicago truncatula.

Transcription factors from the WOX family are well-known regulators of cell proliferation and differentiation in plants. Herein, we focused on several WOX genes from the intermediate clade and checked their impact on somatic embryogenesis using the model legume object Medicago truncatula. As a result, we show that MtWOX9-1 overexpression not only stimulates somatic embryogenesis in the embryogenic M. truncatula line, as it was shown previously, but can also induce somatic embryogenesis in the non-embryogenic line. Other intermediate clade WOX, including the close paralog of MtWOX9-1, as well as WOX11 homologs, did not have any significant impact on somatic embryogenesis in our in vitro cultivation system. Together, our results give new information about the diversity of the WOX family proteins and their specific functions. These data can be used for the search of new regeneration stimulators.

Exploring the potential mechanism and molecular targets of Taohong Siwu Decoction against deep vein thrombosis based on network pharmacology and analysis docking.

This study aims to investigate the mechanism of Taohong Siwu Decoction (THSWD) against deep vein thrombosis (DVT) using network pharmacology and molecular docking technology. We used the Traditional Chinese Medicine Systems Pharmacology database and reviewed literature to identify the main chemical components of THSWD. To find targets for DVT, we consulted GeneCards, Therapeutic Target Database, and PharmGKB databases. We used Cytoscape 3.8.2 software to construct herb-disease-gene-target networks. Additionally, we integrated drug targets and disease targets on the STRING platform to create a protein-protein interaction network. Then, we conducted Kyoto Encyclopedia of Genes and Genomes and gene ontology analysis. Finally, We employed the molecular docking method to validate our findings. We identified 56 potential targets associated with DVT and found 61 effective components. beta-sitosterol, quercetin, and kaempferol were the most prominent among these components. Our analysis of the protein-protein interaction network revealed that IL6, L1B, and AKT1 had the highest degree of association. Gene ontology analysis showed that THSWD treatment for DVT may involve response to inorganic substances, negative regulation of cell differentiation, plasma membrane protein complex, positive regulation of phosphorylation, and signaling receptor regulator activity. Kyoto Encyclopedia of Genes and Genomes analysis indicated that lipid and atherosclerosis, pathways in cancer, as well as the PI3K-Akt pathway are the main signal pathways involved. Molecular docking results demonstrated strong binding affinity between beta-sitosterol, quercetin, kaempferol, and AKT1 proteins as well as IL1B and IL6 proteins. The main targets for THSWD treatment of DVT may include AKT1, IL1B, and IL6. Beta-sitosterol, quercetin, and kaempferol may be the active ingredients responsible for producing this effect. These compounds may slow down the progression of DVT by regulating the inflammatory response through the PI3K/Akt pathway.

Characterization of Commercially Available Human Primary Alveolar Epithelial Cells.

In vitro lung research requires appropriate cell culture models that adequately mimic invivo structure and function. Previously, researchers extensively used commercially available and easily expandable A549 and NCI-H441 cells, which replicate some but not all features of alveolar epithelial cells. Specifically, these cells are often restricted by terminally altered expression while lacking important alveolar epithelial characteristics. Of late, human primary alveolar epithelial cells (hPAEpCs) have become commercially available but are so far poorly specified. Here, we applied a comprehensive set of technologies to characterize their morphology, surface marker expression, transcriptomic profile, and functional properties. At optimized seeding numbers of 7,500 cells per square centimeter and growth at a gas-liquid interface, hPAEpCs formed regular monolayers with tight junctions and amiloride-sensitive transepithelial ion transport. Electron microscopy revealed lamellar body and microvilli formation characteristic for alveolar type II cells. Protein and single-cell transcriptomic analyses revealed expression of alveolar type I and type II cell markers; yet, transcriptomic data failed to detect NKX2-1, an important transcriptional regulator of alveolar cell differentiation. With increasing passage number, hPAEpCs transdifferentiated toward alveolar-basal intermediates characterized as SFTPC-, KRT8high, and KRT5- cells. In spite of marked changes in the transcriptome as a function of passaging, Uniform Manifold Approximation and Projection plots did not reveal major shifts in cell clusters, and epithelial permeability was unaffected. The present work delineates optimized culture conditions, cellular characteristics, and functional properties of commercially available hPAEpCs. hPAEpCs may provide a useful model system for studies on drug delivery, barrier function, and transepithelial ion transport invitro.

Piezoelectric Nanomaterial‐Mediated Physical Signals Regulate Cell Differentiation for Regenerative Medicine

Tissue damage often causes considerable suffering to patients due to slow recovery and poor prognosis. The use of electroactive materials to deliver biophysical signals plays a key role in regulating tissue regeneration processes. Among these materials, piezoelectric materials have unique electromechanical conversion capabilities, making them suitable for use as cell scaffolds. They can deform and emit electrical signals in response to external stimuli, thereby regulating cell proliferation and differentiation. In this review, recent advances are presented in piezoelectric materials as physical signaling mediators that regulate cell differentiation. The basic mechanisms, classification of these materials, and their different applications in tissue regeneration are described. Finally, a comprehensive discussion of current challenges and prospects in the field is provided. Together, existing experimental results basically show that piezoelectric materials can improve the process and effect of tissue repair, providing new technical options for the development of tissue engineering in the future.

PRDM16 regulates γδT17 cell differentiation via controlling type 17 program and lipid-dependent cell fitness.

γδT17 cells are a subset of γδT cells producing IL-17, which is crucial for protection against bacterial and fungal infections. It has recently been shown that γδT17 cells have enriched lipid storage and lipid metabolism. However, the regulation of γδT17 cell function and differentiation with respect to lipids remains unknown. Here, we report that PRDM16 is a critical regulator of γδT17 cell differentiation, controlling type 17 immunity gene expression program and lipid-dependent cell fitness. We demonstrated that γδT17 cells have higher lipid-dependent cell fitness, which is negatively correlated with the expression of Prdm16. Loss of Prdm16 enhances the function and differentiation of γδT17 cells, and increases their fitness in lipid-rich environments. Specifically, loss of Prdm16 exacerbates development of psoriasis in the skin, a lipid-rich organ, and Prdm16 controls lipid-mediated differentiation of Vγ4+ γδT17 cells, which are the major source of IL-17 during the onset of psoriasis. Our study highlights the potential impact of PRDM16 on lipid-dependent fitness and protective immune function of γδT cells and also on the immunotherapy of psoriasis and inflammatory diseases.