Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.

• MeSH
• Neural Crest MeSH
• Forkhead Transcription Factors metabolism   genetics   MeSH
• Homeodomain Proteins * metabolism   genetics   MeSH
• Mesoderm * metabolism   MeSH
• Mice MeSH
• Trigeminal Nerve * MeSH
• Vibrissae * innervation   growth & development   embryology   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Fibroblasts, the most abundant cell type in the human body, play crucial roles in biological processes such as inflammation and cancer progression. They originate from the mesoderm or neural-crest-derived ectomesenchyme. Ectomesenchyme-derived fibroblasts contribute to facial formation and do not express HOX genes during development. The expression and role of the HOX genes in adult fibroblasts is not known. We investigated whether the developmental pattern persists into adulthood and under pathological conditions, such as cancer. We collected adult fibroblasts of ectomesenchymal and mesodermal origins from distinct body parts. The isolated fibroblasts were characterised by immunocytochemistry, and their transcriptome was analysed by whole genome profiling. Significant differences were observed between normal fibroblasts from the face (ectomesenchyme) and upper limb (mesoderm), particularly in genes associated with limb development, including HOX genes, e.g., HOXA9 and HOXD9. Notably, the pattern of HOX gene expression remained consistent postnatally, even in fibroblasts from pathological tissues, including inflammatory states and cancer-associated fibroblasts from primary and metastatic tumours. Therefore, the distinctive HOX gene expression pattern can serve as an indicator of the topological origin of fibroblasts. The influence of cell position and HOX gene expression in fibroblasts on disease progression warrants further investigation.

• MeSH
• Adult MeSH
• Fibroblasts * metabolism   cytology   MeSH
• Genes, Homeobox MeSH
• Homeodomain Proteins metabolism   genetics   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Mesoderm * metabolism   cytology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   MeSH
• DNA-Directed DNA Polymerase genetics   metabolism   MeSH
• DNA Primase genetics   metabolism   MeSH
• Extracellular Matrix metabolism   pathology   MeSH
• Genes, p53 genetics   MeSH
• Glioblastoma metabolism   pathology   MeSH
• Pericytes metabolism   pathology   MeSH
• BRCA1 Protein genetics   metabolism   MeSH
• Publication type
• Overall MeSH

Tick-borne encephalitis virus (TBEV) targets the central nervous system (CNS), leading to potentially severe neurological complications. The neurovascular unit plays a fundamental role in the CNS and in the neuroinvasion of TBEV. However, the role of human brain pericytes, a key component of the neurovascular unit, during TBEV infection has not yet been elucidated. In this study, TBEV infection of the primary human brain perivascular pericytes was investigated with highly virulent Hypr strain and mildly virulent Neudoerfl strain. We used Luminex assay to measure cytokines/chemokines and growth factors. Both viral strains showed comparable replication kinetics, peaking at 3 days post infection (dpi). Intracellular viral RNA copies peaked at 6 dpi for Hypr and 3 dpi for Neudoerfl cultures. According to immunofluorescence staining, only small proportion of pericytes were infected (3% for Hypr and 2% for Neudoerfl), and no cytopathic effect was observed in the infected cells. In cell culture supernatants, IL-6 production was detected at 3 dpi, together with slight increases in IL-15 and IL-4, but IP-10, RANTES and MCP-1 were the main chemokines released after TBEV infection. These chemokines play key roles in both immune defense and immunopathology during TBE. This study suggests that pericytes are an important source of these signaling molecules during TBEV infection in the brain.

• MeSH
• Chemokine CCL5 * metabolism   MeSH
• Chemokine CXCL10 * metabolism   MeSH
• Cytokines metabolism   MeSH
• Encephalitis, Tick-Borne * virology   metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Brain * virology   metabolism   pathology   MeSH
• Pericytes * virology   metabolism   MeSH
• Virus Replication MeSH
• Encephalitis Viruses, Tick-Borne * physiology   pathogenicity   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Gliomagenesis induces profound changes in the composition of the extracellular matrix (ECM) of the brain. In this study, we identified a cellular population responsible for the increased deposition of collagen I and fibronectin in glioblastoma. Elevated levels of the fibrillar proteins collagen I and fibronectin were associated with the expression of fibroblast activation protein (FAP), which is predominantly found in pericyte-like cells in glioblastoma. FAP+ pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in the GBM microenvironment. Using mass spectrometry, we demonstrated that 3D matrices produced by FAP+ pericyte-like cells are rich in collagen I and fibronectin and contain several basement membrane proteins. This expression pattern differed markedly from glioma cells. Finally, we have shown that ECM produced by FAP+ pericyte-like cells enhances the migration of glioma cells including glioma stem-like cells, promotes their adhesion, and activates focal adhesion kinase (FAK) signaling. Taken together, our findings establish FAP+ pericyte-like cells as crucial producers of a complex ECM rich in collagen I and fibronectin, facilitating the dissemination of glioma cells through FAK activation.

• MeSH
• Endopeptidases MeSH
• Extracellular Matrix * metabolism   pathology   MeSH
• Fibronectins * metabolism   MeSH
• Glioblastoma pathology   metabolism   MeSH
• Glioma * pathology   metabolism   MeSH
• Collagen Type I metabolism   MeSH
• Humans MeSH
• Membrane Proteins metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment physiology   MeSH
• Brain Neoplasms * pathology   metabolism   MeSH
• Pericytes * metabolism   pathology   MeSH
• Cell Movement physiology   MeSH
• Serine Endopeptidases metabolism   MeSH
• Gelatinases metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Drug delivery to central nervous pathologies is compromised by the blood-brain barrier (BBB). A clinically explored strategy to promote drug delivery across the BBB is sonopermeation, which relies on the combined use of ultrasound (US) and microbubbles (MB) to induce temporally and spatially controlled opening of the BBB. We developed an advanced in vitro BBB model to study the impact of sonopermeation on the delivery of the prototypic polymeric drug carrier pHPMA as a larger molecule and the small molecule antiviral drug ribavirin. This was done under standard and under inflammatory conditions, employing both untargeted and RGD peptide-coated MB. The BBB model is based on human cerebral capillary endothelial cells and human placental pericytes, which are co-cultivated in transwell inserts and which present with proper transendothelial electrical resistance (TEER). Sonopermeation induced a significant decrease in TEER values and facilitated the trans-BBB delivery of fluorescently labeled pHPMA (Atto488-pHPMA). To study drug delivery under inflamed endothelial conditions, which are typical for e.g. tumors, neurodegenerative diseases and CNS infections, tumor necrosis factor (TNF) was employed to induce inflammation in the BBB model. RGD-coated MB bound to and permeabilized the inflamed endothelium-pericyte co-culture model, and potently improved Atto488-pHPMA and ribavirin delivery. Taken together, our work combines in vitro BBB bioengineering with MB-mediated drug delivery enhancement, thereby providing a framework for future studies on optimization of US-mediated drug delivery to the brain.

• MeSH
• Antiviral Agents administration & dosage   chemistry   pharmacology   pharmacokinetics   MeSH
• Endothelial Cells * drug effects   metabolism   MeSH
• Blood-Brain Barrier * metabolism   MeSH
• Coculture Techniques * MeSH
• Drug Delivery Systems methods   MeSH
• Humans MeSH
• Microbubbles * MeSH
• Oligopeptides * chemistry   administration & dosage   pharmacokinetics   MeSH
• Pericytes * metabolism   drug effects   MeSH
• Polymers chemistry   administration & dosage   MeSH
• Ribavirin administration & dosage   chemistry   pharmacokinetics   MeSH
• Ultrasonic Waves MeSH
• Inflammation drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Lung fibrosis is a serious human pathology. MiR-146b-5p is down-regulated in idiopathic pulmonary fibrosis, and the Notch1/PDGFRβ/ROCK1 pathway is activated. However, the relation between miR-146b-5p and the Notch1/PDGFRβ/ROCK1 pathway in lung fibrosis remains unclear. To investigate the function of miR-146b-5p in lung fibrosis, an in vivo model of lung fibrosis was established in mice by bleomycin. The fibrosis in lung tissues of mice was observed by HE, Masson and Sirius Red staining. Lung pericytes were isolated and identified by fluorescence microscopy. Immunofluorescence staining and Western blot were used to investigate the expression of desmin, NG2, collagen I and α-SMA. CCK8 assay was used to assess the cell viability, and flow cytometry was performed to evaluate the cell cycle in pericytes. Furthermore, the correlation between miR-146b-5p and Notch1 was analysed by Spearman analysis. The mechanism by which miR-146b-5p affects pericytes and lung fibrosis via the Notch1/ PDGFRβ/ROCK1 pathway was explored by RT-qPCR, Western blot, immunofluorescence staining and dual luciferase reporter gene assay. In bleomycin-treated mice, miR-146b-5p was down-regulated, while Notch1 was up-regulated. Up-regulation of miR-146b-5p significantly inhibited the viability and induced G1 phase arrest of lung pericytes. MiR-146b-5p mimics up-regulated miR-146b-5p, desmin, and NG2 and down-regulated α-SMA and collagen I in the lung pericytes. Additionally, miR-146b-5p was negatively correlated with Notch1, and miR-146b-5p interacted with Notch1. Over-expression of miR-146b-5p inactivated the Notch1/PDGFRβ/ROCK1 pathway. Our results indicate that up-regulation of miR-146b-5p inhibits fibrosis in lung pericytes via modulation of the Notch1/PDGFRβ/ROCK1 pathway. Thus, our study might provide a novel target against lung fibrosis.

• MeSH
• Bleomycin metabolism   MeSH
• Desmin genetics   metabolism   MeSH
• rho-Associated Kinases genetics   metabolism   MeSH
• Collagen genetics   metabolism   MeSH
• Humans MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Mice MeSH
• Pericytes metabolism   pathology   MeSH
• Lung metabolism   pathology   MeSH
• Pulmonary Fibrosis * genetics   metabolism   pathology   MeSH
• Receptor, Notch1 genetics   metabolism   MeSH
• Up-Regulation genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Fibroepiteliální polypy jsou benigní nádory vycházející z pojivové tkáně. Jsou mezodermálního původu, kryté obvykle dlaždicovým epitelem, nejčastěji se nacházejí na kůži, v urogenitálním traktu nebo v oblasti dolních cest dýchacích. Mohou být ojedinělé nebo vícečetné. Jejich rozměry obvykle nepřesahují 1-2 milimetry. Zcela výjimečně mohou dosahovat obrovských rozměrů. V literatuře byl popsán obří fibroepiteliální polyp o velikosti 42 centimetrů. Přestože etiologie a faktory způsobující nadměrný růst nebyly objasněny, uvádí se, že růst může vyvolat především chronické mechanické dráždění, obezita a inzulinová rezistence, lymfatická stagnace a chronický zánět. Možnosti odstranění těchto projevů jsou chirurgické snesení, laserové ablace, elektrokauterizace, kryodestrukce a další. Existují i možnosti domácího ošetření. Vždy je však nutná pečlivá diagnostika.

Fibroepithelial polyps are benign tumors arising from connective tissue. They are of mesodermal origin and are usually covered with squamous epithelium and come from the skin, genitourinary tract or lower respiratory tract. On the skin, they occur mainly in the skin folds. They can be isolated or multiple. They are usually no larger than 1-2 millimeters. In rare cases, they can reach enormous dimensions. A giant fibroepithelial polyp 42 centimeters in size has been described in the literature. Although the etiology and factors causing overgrowth are not known, an association with chronic mechanical irritation, obesity, insulin resistance, as well as prolonged lymphatic stagnation and chronic inflammation has been reported. Types of removal of these symptoms are surgical excision, laser ablation, electrocauter destruction, cryodestruction and more. There are also home treatment options. However, careful diagnosis is always necessary.

• MeSH
• Birt-Hogg-Dube Syndrome therapy   MeSH
• Dermatologic Surgical Procedures MeSH
• Electrocoagulation MeSH
• Neoplasms, Fibroepithelial * diagnosis   therapy   MeSH
• Fibroma therapy   MeSH
• Hamartoma therapy   MeSH
• Cryotherapy methods   MeSH
• Laser Therapy MeSH
• Humans MeSH
• Mesoderm pathology   MeSH
• Polyps * therapy   MeSH
• Hamartoma Syndrome, Multiple therapy   MeSH
• Check Tag
• Humans MeSH

The tight regulation of cytoskeleton dynamics is required for a number of cellular processes, including migration, division and differentiation. YAP-TEAD respond to cell-cell interaction and to substrate mechanics and, among their downstream effects, prompt focal adhesion (FA) gene transcription, thus contributing to FA-cytoskeleton stability. This activity is key to the definition of adult cell mechanical properties and function. Its regulation and role in pluripotent stem cells are poorly understood. Human PSCs display a sustained basal YAP-driven transcriptional activity despite they grow in very dense colonies, indicating these cells are insensitive to contact inhibition. PSC inability to perceive cell-cell interactions can be restored by tampering with Tankyrase enzyme, thus favouring AMOT inhibition of YAP function. YAP-TEAD complex is promptly inactivated when germ layers are specified, and this event is needed to adjust PSC mechanical properties in response to physiological substrate stiffness. By providing evidence that YAP-TEAD1 complex targets key genes encoding for proteins involved in cytoskeleton dynamics, we suggest that substrate mechanics can direct PSC specification by influencing cytoskeleton arrangement and intracellular tension. We propose an aberrant activation of YAP-TEAD1 axis alters PSC potency by inhibiting cytoskeleton dynamics, thus paralyzing the changes in shape requested for the acquisition of the given phenotype.

• MeSH
• Adaptor Proteins, Signal Transducing MeSH
• Angiomotins metabolism   MeSH
• Cell Differentiation MeSH
• Cell Line MeSH
• Cytoskeleton metabolism   MeSH
• Humans MeSH
• Human Embryonic Stem Cells metabolism   MeSH
• Mesoderm metabolism   MeSH
• YAP-Signaling Proteins genetics   metabolism   MeSH
• Signal Transduction MeSH
• TEA Domain Transcription Factors genetics   metabolism   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

We lack a holistic understanding of the genetic programs orchestrating embryonic colon morphogenesis and governing damage response in the adult. A window into these programs is the transcriptomes of the epithelial and mesenchymal cell populations in the colon. Performing unbiased single-cell transcriptomic analyses of the developing mouse colon at different embryonic stages (embryonic day 14.5 [E14.5], E15.5, and E18.5), we capture cellular and molecular profiles of the stages before, during, and after the appearance of crypt structures, as well as in a model of adult colitis. The data suggest most adult lineages are established by E18.5. We find embryonic-specific gene expression profiles and cell populations that reappear in response to tissue damage. Comparison of the datasets from mice and human colitis suggests the processes are conserved. In this study, we provide a comprehensive single-cell atlas of the developing mouse colon and evidence for the reactivation of embryonic genes in disease.

• MeSH
• Single-Cell Analysis MeSH
• Cell Differentiation MeSH
• Embryo, Mammalian metabolism   MeSH
• Inflammatory Bowel Diseases genetics   pathology   MeSH
• Colitis genetics   MeSH
• Colon embryology   pathology   MeSH
• Humans MeSH
• Mesoderm embryology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Gene Expression Profiling * MeSH
• Intestinal Mucosa embryology   metabolism   pathology   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH