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Cell Jun 2024Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi,...
Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.
Topics: Animals; Mice; Intestinal Mucosa; Extracellular Matrix; Myosin Type II; Mesoderm; Mesenchymal Stem Cells; Receptor, Platelet-Derived Growth Factor alpha; Morphogenesis; Matrix Metalloproteinases
PubMed: 38781967
DOI: 10.1016/j.cell.2024.04.039 -
Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target.FASEB Journal : Official Publication of... May 2024Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The... (Review)
Review
Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The pathogenesis of RVD involves vessel dilatation, leakage, and occlusion; however, the specific underlying mechanisms remain unclear. Recent findings have indicated that pericytes (PCs), as critical members of the vascular mural cells, significantly contribute to the progression of RVDs, including detachment from microvessels, alteration of contractile and secretory properties, and excessive production of the extracellular matrix. Moreover, PCs are believed to have mesenchymal stem properties and, therefore, might contribute to regenerative therapy. Here, we review novel ideas concerning PC characteristics and functions in RVDs and discuss potential therapeutic strategies based on PCs, including the targeting of pathological signals and cell-based regenerative treatments.
Topics: Pericytes; Humans; Animals; Retinal Vessels; Retinal Diseases; Diabetic Retinopathy
PubMed: 38780117
DOI: 10.1096/fj.202302624R -
Biochemical Society Transactions Jun 2024Myocardial cell fate specification takes place during the early stages of heart development as the precardiac mesoderm is configured into two symmetrical sets of... (Review)
Review
Myocardial cell fate specification takes place during the early stages of heart development as the precardiac mesoderm is configured into two symmetrical sets of bilateral precursor cells. Molecular cues of the surrounding tissues specify and subsequently determine the early cardiomyocytes, that finally matured as the heart is completed at early postnatal stages. Over the last decade, we have greatly enhanced our understanding of the transcriptional regulation of cardiac development and thus of myocardial cell fate. The recent discovery of a novel layer of gene regulation by non-coding RNAs has flourished their implication in epigenetic, transcriptional and post-transcriptional regulation of cardiac development. In this review, we revised the current state-of-the-art knowledge on the functional role of non-coding RNAs during myocardial cell fate.
Topics: Humans; Animals; Myocytes, Cardiac; RNA, Untranslated; Cell Differentiation; Gene Expression Regulation, Developmental; Myocardium; Heart; Epigenesis, Genetic; Cell Lineage
PubMed: 38775188
DOI: 10.1042/BST20231216 -
Indian Journal of Ophthalmology May 2024The caruncle is a unique anatomical site in the human body, comprising various structures derived from the surface ectoderm and mesoderm. Caruncular lesions can range...
PURPOSE
The caruncle is a unique anatomical site in the human body, comprising various structures derived from the surface ectoderm and mesoderm. Caruncular lesions can range from benign to malignant and present challenges in accurate diagnosis and timely management due to their hidden nature and proximity to the lacrimal sac. This study aims to provide a comprehensive description of caruncular lesions, presenting the first Indian case series on this topic.
METHODS
Ethical approval was obtained, and data collection was conducted at a tertiary care center in India. A retrospective analysis was performed on 44 patients with caruncular lesions treated between 2013 and 2020. Detailed patient histories, clinical examinations, slit lamp imaging, and excision biopsies were conducted. Histopathological examination of the specimens was carried out.
RESULTS
The study included 42 cases of caruncular lesions, with a mean age of 31.09 years. The majority of cases were male (54.54%). Benign lesions accounted for 84.09% of the cases, while premalignant and malignant lesions accounted for 11.36% and 4.54%, respectively. Papilloma and nevus were the most common lesions, with 11 cases each. All caruncular lesions were successfully and completely excised without complications. Histopathological examination confirmed the accuracy of the diagnoses, with an 84.09% concordance rate between clinical assessment and pathological diagnosis.
CONCLUSION
This case series reveals a predominance of benign lesions among individuals in their early thirties. The successful excision of all lesions with a high concordance rate between clinical assessment and histopathological diagnosis underscores the importance of timely and accurate management.
PubMed: 38770617
DOI: 10.4103/IJO.IJO_2088_23 -
Cellular and Molecular Life Sciences :... May 2024Ischemic stroke induces neovascularization of the injured tissue as an attempt to promote structural repair and neurological recovery. Angiogenesis is regulated by...
Ischemic stroke induces neovascularization of the injured tissue as an attempt to promote structural repair and neurological recovery. Angiogenesis is regulated by pericytes that potently react to ischemic stroke stressors, ranging from death to dysfunction. Platelet-derived growth factor (PDGF) receptor (PDGFR)β controls pericyte survival, migration, and interaction with brain endothelial cells. PDGF-D a specific ligand of PDGFRβ is expressed in the brain, yet its regulation and role in ischemic stroke pathobiology remains unexplored. Using experimental ischemic stroke mouse model, we found that PDGF-D is transiently induced in brain endothelial cells at the injury site in the subacute phase. To investigate the biological significance of PDGF-D post-ischemic stroke regulation, its subacute expression was either downregulated using siRNA or upregulated using an active recombinant form. Attenuation of PDGF-D subacute induction exacerbates neuronal loss, impairs microvascular density, alters vascular permeability, and increases microvascular stalling. Increasing PDGF-D subacute bioavailability rescues neuronal survival and improves neurological recovery. PDGF-D subacute enhanced bioavailability promotes stable neovascularization of the injured tissue and improves brain perfusion. Notably, PDGF-D enhanced bioavailability improves pericyte association with brain endothelial cells. Cell-based assays using human brain pericyte and brain endothelial cells exposed to ischemia-like conditions were applied to investigate the underlying mechanisms. PDGF-D stimulation attenuates pericyte loss and fibrotic transition, while increasing the secretion of pro-angiogenic and vascular protective factors. Moreover, PDGF-D stimulates pericyte migration required for optimal endothelial coverage and promotes angiogenesis. Our study unravels new insights into PDGF-D contribution to neurovascular protection after ischemic stroke by rescuing the functions of pericytes.
Topics: Pericytes; Animals; Ischemic Stroke; Mice; Lymphokines; Platelet-Derived Growth Factor; Humans; Endothelial Cells; Male; Mice, Inbred C57BL; Brain; Disease Models, Animal; Neovascularization, Physiologic; Cell Movement
PubMed: 38769116
DOI: 10.1007/s00018-024-05244-w -
ACS Nano Jun 2024Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a...
Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.
Topics: Alzheimer Disease; Animals; Pericytes; Mice; Mice, Transgenic; Reactive Oxygen Species; Curcumin; Prodrugs; Nanoparticles; Vascular Cell Adhesion Molecule-1; Humans; Peptides; Neuroprotective Agents
PubMed: 38768086
DOI: 10.1021/acsnano.4c00480 -
The EMBO Journal Jun 2024How cells coordinate morphogenetic cues and fate specification during development remains a fundamental question in organogenesis. The mammary gland arises from...
How cells coordinate morphogenetic cues and fate specification during development remains a fundamental question in organogenesis. The mammary gland arises from multipotent stem cells (MaSCs), which are progressively replaced by unipotent progenitors by birth. However, the lack of specific markers for early fate specification has prevented the delineation of the features and spatial localization of MaSC-derived lineage-committed progenitors. Here, using single-cell RNA sequencing from E13.5 to birth, we produced an atlas of matched mouse mammary epithelium and mesenchyme and reconstructed the differentiation trajectories of MaSCs toward basal and luminal fate. We show that murine MaSCs exhibit lineage commitment just prior to the first sprouting events of mammary branching morphogenesis at E15.5. We identify early molecular markers for committed and multipotent MaSCs and define their spatial distribution within the developing tissue. Furthermore, we show that the mammary embryonic mesenchyme is composed of two spatially restricted cell populations, and that dermal mesenchyme-produced FGF10 is essential for embryonic mammary branching morphogenesis. Altogether, our data elucidate the spatiotemporal signals underlying lineage specification of multipotent MaSCs, and uncover the signals from mesenchymal cells that guide mammary branching morphogenesis.
Topics: Animals; Mice; Mammary Glands, Animal; Female; Cell Lineage; Mesenchymal Stem Cells; Epithelial Cells; Cell Differentiation; Multipotent Stem Cells; Fibroblast Growth Factor 10; Morphogenesis; Single-Cell Analysis; Mesoderm
PubMed: 38760574
DOI: 10.1038/s44318-024-00115-3 -
Development (Cambridge, England) May 2024Collective migration of caudal visceral mesoderm (CVM) cells in Drosophila embryos helps form the longitudinal muscles of the larval gut. In their study, Angelike...
Collective migration of caudal visceral mesoderm (CVM) cells in Drosophila embryos helps form the longitudinal muscles of the larval gut. In their study, Angelike Stathopoulos and colleagues reveal that cell division coordinates two gene expression programmes in migrating CVM cells. To know more about their work, we spoke to the first author, Jingjing Sun, and the corresponding author, Angelike Stathopoulos, Professor in the Division of Biology at the California Institute of Technology, USA.
Topics: Animals; Developmental Biology; History, 20th Century; History, 21st Century; Mesoderm; Drosophila; Cell Movement; Humans
PubMed: 38757779
DOI: 10.1242/dev.203022 -
Nature Communications May 2024Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is essential for the development of new organ systems, but transcriptional control of...
Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is essential for the development of new organ systems, but transcriptional control of angiogenesis remains incompletely understood. Here we show that FOXC1 is essential for retinal angiogenesis. Endothelial cell (EC)-specific loss of Foxc1 impairs retinal vascular growth and expression of Slc3a2 and Slc7a5, which encode the heterodimeric CD98 (LAT1/4F2hc) amino acid transporter and regulate the intracellular transport of essential amino acids and activation of the mammalian target of rapamycin (mTOR). EC-Foxc1 deficiency diminishes mTOR activity, while administration of the mTOR agonist MHY-1485 rescues perturbed retinal angiogenesis. EC-Foxc1 expression is required for retinal revascularization and resolution of neovascular tufts in a model of oxygen-induced retinopathy. Foxc1 is also indispensable for pericytes, a critical component of the blood-retina barrier during retinal angiogenesis. Our findings establish FOXC1 as a crucial regulator of retinal vessels and identify therapeutic targets for treating retinal vascular disease.
Topics: Animals; Forkhead Transcription Factors; Retinal Neovascularization; Mice; Endothelial Cells; Blood-Retinal Barrier; TOR Serine-Threonine Kinases; Pericytes; Fusion Regulatory Protein 1, Heavy Chain; Retinal Vessels; Humans; Large Neutral Amino Acid-Transporter 1; Mice, Knockout; Mice, Inbred C57BL; Retina; Male; Angiogenesis
PubMed: 38755144
DOI: 10.1038/s41467-024-48134-2 -
Microbiology Spectrum Jun 2024Enterovirus A71 (EV-A71) is associated with neurological conditions such as acute meningitis and encephalitis. The virus is detected in the bloodstream, and high blood...
Enterovirus A71 (EV-A71) is associated with neurological conditions such as acute meningitis and encephalitis. The virus is detected in the bloodstream, and high blood viral loads are associated with central nervous system (CNS) manifestations. We used an blood-brain barrier (BBB) model made up of human brain-like endothelial cells (hBLECs) and brain pericytes grown in transwell systems to investigate whether three genetically distinct EV-A71 strains (subgenogroups C1, C1-like, and C4) can cross the human BBB. EV-A71 poorly replicated in hBLECs, which released moderate amounts of infectious viruses from their luminal side and trace amounts of infectious viruses from their basolateral side. The barrier properties of hBLECs were not impaired by EV-A71 infection. We investigated the passage through hBLECs of EV-A71-infected white blood cells. EV-A71 strains efficiently replicated in immune cells, including monocytes, neutrophils, and NK/T cells. Attachment to hBLECs of immune cells infected with the C1-like virus was higher than attachment of cells infected with C1-06. EV-A71 infection did not impair the transmigration of immune cells through hBLECs. Overall, EV-A71 targets different white blood cell populations that have the potential to be used as a Trojan horse to cross hBLECs more efficiently than cell-free EV-A71 particles.IMPORTANCEEnterovirus A71 (EV-A71) was first reported in the USA, and numerous outbreaks have since occurred in Asia and Europe. EV-A71 re-emerged as a new multirecombinant strain in 2015 in Europe and is now widespread. The virus causes hand-foot-and-mouth disease in young children and is involved in nervous system infections. How the virus spreads to the nervous system is unclear. We investigated whether white blood cells could be infected by EV-A71 and transmit it across human endothelial cells mimicking the blood-brain barrier protecting the brain from adverse effects. We found that endothelial cells provide a strong roadblock to prevent the passage of free virus particles but allow the migration of infected immune cells, including monocytes, neutrophils, and NK/T cells. Our data are consistent with the potential role of immune cells in the pathogenesis of EV-A71 infections by spreading the virus in the blood and across the human blood-brain barrier.
Topics: Blood-Brain Barrier; Humans; Enterovirus A, Human; Enterovirus Infections; Endothelial Cells; Virus Replication; Monocytes; Pericytes; Leukocytes; Brain; Killer Cells, Natural; Neutrophils
PubMed: 38752731
DOI: 10.1128/spectrum.00690-24