-
Open Biology Jun 2024Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A...
Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A major route by which COVID-19 impacts different organs is via the vascular system. We studied the impact of apolipoprotein E (APOE) genotype and inflammation on vascular infectivity by pseudo-typed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses in mouse and human cultured endothelial cells and pericytes. Possessing the APOE4 allele or having existing systemic inflammation is known to enhance the severity of COVID-19. Using targeted replacement human APOE3 and APOE4 mice and inflammation induced by bacterial lipopolysaccharide (LPS), we investigated infection by SARS-CoV-2. Here, we show that infectivity was higher in murine cerebrovascular pericytes compared to endothelial cells and higher in cultures expressing APOE4. Furthermore, increasing the inflammatory state of the cells by prior incubation with LPS increased infectivity into human and mouse pericytes and human endothelial cells. Our findings provide insights into the mechanisms underlying severe COVID-19 infection, highlighting how risk factors such as APOE4 genotype and prior inflammation may exacerbate disease severity by augmenting the virus's ability to infect vascular cells.
Topics: Pericytes; Humans; Animals; SARS-CoV-2; COVID-19; Mice; Endothelial Cells; Risk Factors; Lipopolysaccharides; Apolipoprotein E4; Apolipoprotein E3; Inflammation
PubMed: 38862017
DOI: 10.1098/rsob.230349 -
Reproductive Toxicology (Elmsford, N.Y.) Jun 2024Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals...
Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals result from complex chemical-biological interactions, and while New Approach Methods (NAMs) based on in vitro bioactivity profiles of human cells offer promising alternatives to animal testing, most of these assays lack cellular positional information, physical constraints, and regional organization of the intact embryo. Here, we engineered a fully computable model of the embryonic disc in the CompuCell3D.org modeling environment to simulate epithelial-mesenchymal transition (EMT) of epiblast cells and self-organization of mesodermal domains (chordamesoderm, paraxial, lateral plate, posterior/extraembryonic). Mesodermal fate is modeled by synthetic activity of the BMP4-NODAL-WNT signaling axis. Cell position in the epiblast determines timing with respect to EMT for 988 computational cells in the computer model. An autonomous homeobox (Hox) clock hidden in the epiblast is driven by WNT-FGF4-CDX signaling. Executing the model renders a quantitative cell-level computation of mesodermal fate and consequences of perturbation based on known biology. For example, synthetic perturbation of the control network rendered altered phenotypes (cybermorphs) mirroring some aspects of experimental mouse embryology, with electronic knockouts, under-activation (hypermorphs) or over-activation (hypermorphs) particularly affecting the size and specification of the posterior mesoderm. This foundational model is trained on embryology but capable of performing a wide variety of toxicological tasks conversing through anatomical simulation to integrate in vitro chemical bioactivity data with known embryology. It is amenable to quantitative simulation for probabilistic prediction of early developmental toxicity.
PubMed: 38857815
DOI: 10.1016/j.reprotox.2024.108625 -
ELife Jun 2024Erectile dysfunction (ED) affects a significant proportion of men aged 40-70 and is caused by cavernous tissue dysfunction. Presently, the most common treatment for ED...
Erectile dysfunction (ED) affects a significant proportion of men aged 40-70 and is caused by cavernous tissue dysfunction. Presently, the most common treatment for ED is phosphodiesterase 5 inhibitors; however, this is less effective in patients with severe vascular disease such as diabetic ED. Therefore, there is a need for development of new treatment, which requires a better understanding of the cavernous microenvironment and cell-cell communications under diabetic condition. Pericytes are vital in penile erection; however, their dysfunction due to diabetes remains unclear. In this study, we performed single-cell RNA sequencing to understand the cellular landscape of cavernous tissues and cell type-specific transcriptional changes in diabetic ED. We found a decreased expression of genes associated with collagen or extracellular matrix organization and angiogenesis in diabetic fibroblasts, chondrocytes, myofibroblasts, valve-related lymphatic endothelial cells, and pericytes. Moreover, the newly identified pericyte-specific marker, Limb Bud-Heart (Lbh) in mouse and human cavernous tissues, clearly distinguishing pericytes from smooth muscle cells. Cell-cell interaction analysis revealed that pericytes are involved in angiogenesis, adhesion, and migration by communicating with other cell types in the corpus cavernosum; however, these interactions were highly reduced under diabetic conditions. Lbh expression is low in diabetic pericytes, and overexpression of LBH prevents erectile function by regulating neurovascular regeneration. Furthermore, the LBH-interacting proteins (Crystallin Alpha B and Vimentin) were identified in mouse cavernous pericytes through LC-MS/MS analysis, indicating that their interactions were critical for maintaining pericyte function. Thus, our study reveals novel targets and insights into the pathogenesis of ED in patients with diabetes.
Topics: Male; Pericytes; Erectile Dysfunction; Single-Cell Analysis; Animals; Mice; Humans; Penis; Gene Expression Profiling; Transcriptome; Mice, Inbred C57BL; Single-Cell Gene Expression Analysis
PubMed: 38856719
DOI: 10.7554/eLife.88942 -
ELife Jun 2024Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result...
Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.
Topics: Animals; Bone Morphogenetic Protein Receptors, Type I; Signal Transduction; Mice; Mice, Knockout; Lung; Mesoderm; Cysts; Bone Morphogenetic Proteins; Lung Diseases; Disease Models, Animal
PubMed: 38856718
DOI: 10.7554/eLife.91876 -
Development (Cambridge, England) Jun 2024A major challenge in biology is to understand how mechanical interactions and cellular behavior affect the shapes of tissues and embryo morphology. The extension of the...
A major challenge in biology is to understand how mechanical interactions and cellular behavior affect the shapes of tissues and embryo morphology. The extension of the neural tube and paraxial mesoderm, which form the spinal cord and musculoskeletal system respectively, results in the elongated shape of the vertebrate embryonic body. Despite our understanding of how each of these tissues elongates independently of the others, the morphogenetic consequences of their simultaneous growth and mechanical interactions are still unclear. Our study investigates how differential growth, tissue biophysical properties, and mechanical interactions affect embryonic morphogenesis during axial extension using a 2D multi-tissue continuum-based mathematical model. Our model captures the dynamics observed in vivo by time-lapse imaging of bird embryos and reveals the underestimated influence of differential tissue proliferation rates. We confirmed this prediction in quail embryos by showing that decreasing the rate of cell proliferation in the paraxial mesoderm affects long-term tissue dynamics and shaping of both the paraxial mesoderm and the neighboring neural tube. Overall, our work provides a new theoretical platform to consider the long-term consequences of tissue differential growth and mechanical interactions on morphogenesis.
PubMed: 38856082
DOI: 10.1242/dev.202836 -
Biomedicine & Pharmacotherapy =... Jul 2024Intracranial atherosclerotic stenosis (ICAS) is a pathological condition characterized by progressive narrowing or complete blockage of intracranial blood vessels caused... (Review)
Review
Intracranial atherosclerotic stenosis (ICAS) is a pathological condition characterized by progressive narrowing or complete blockage of intracranial blood vessels caused by plaque formation. This condition leads to reduced blood flow to the brain, resulting in cerebral ischemia and hypoxia. Ischemic stroke (IS) resulting from ICAS poses a significant global public health challenge, especially among East Asian populations. However, the underlying causes of the notable variations in prevalence among diverse populations, as well as the most effective strategies for preventing and treating the rupture and blockage of intracranial plaques, remain incompletely comprehended. Rupture of plaques, bleeding, and thrombosis serve as precipitating factors in the pathogenesis of luminal obstruction in intracranial arteries. Pericytes play a crucial role in the structure and function of blood vessels and face significant challenges in regulating the Vasa Vasorum (VV)and preventing intraplaque hemorrhage (IPH). This review aims to explore innovative therapeutic strategies that target the pathophysiological mechanisms of vulnerable plaques by modulating pericyte biological function. It also discusses the potential applications of pericytes in central nervous system (CNS) diseases and their prospects as a therapeutic intervention in the field of biological tissue engineering regeneration.
Topics: Pericytes; Humans; Animals; Intracranial Arteriosclerosis; Vasa Vasorum; Cerebral Arteries
PubMed: 38850658
DOI: 10.1016/j.biopha.2024.116870 -
Cell Jun 2024Epithelial folding is a fundamental biological process that requires epithelial interactions with the underlying mesenchyme. In this issue of Cell, Huycke et al....
Epithelial folding is a fundamental biological process that requires epithelial interactions with the underlying mesenchyme. In this issue of Cell, Huycke et al. investigate intestinal villus formation. They discover that water-droplet-like behavior of mesenchymal cells drives their coalescence into uniformly patterned aggregates, which generate forces on the epithelium to initiate folding.
Topics: Animals; Humans; Epithelial Cells; Intestinal Mucosa; Mesoderm; Epithelium
PubMed: 38848672
DOI: 10.1016/j.cell.2024.04.045 -
Communications Biology Jun 2024Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary...
Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary Arterial Hypertension (PAH). Augmented expression and action of growth factors trigger these pathological changes. Endogenous factors opposing such alterations are barely known. Here, we examine whether and how the endothelial hormone C-type natriuretic peptide (CNP), signaling through the cyclic guanosine monophosphate (cGMP) -producing guanylyl cyclase B (GC-B) receptor, attenuates the pericyte dysfunction observed in PAH. The results demonstrate that CNP/GC-B/cGMP signaling is preserved in lung pericytes from patients with PAH and prevents their growth factor-induced proliferation, migration, and transdifferentiation. The anti-proliferative effect of CNP is mediated by cGMP-dependent protein kinase I and inhibition of the Phosphoinositide 3-kinase (PI3K)/AKT pathway, ultimately leading to the nuclear stabilization and activation of the Forkhead Box O 3 (FoxO3) transcription factor. Augmentation of the CNP/GC-B/cGMP/FoxO3 signaling pathway might be a target for novel therapeutics in the field of PAH.
Topics: Humans; Pericytes; Natriuretic Peptide, C-Type; Cyclic GMP; Signal Transduction; Forkhead Box Protein O3; Cell Proliferation; Male; Female; Pulmonary Arterial Hypertension; Middle Aged; Hypertension, Pulmonary; Adult; Receptors, Atrial Natriuretic Factor; Cells, Cultured
PubMed: 38844781
DOI: 10.1038/s42003-024-06375-3 -
Journal of Controlled Release :... Jul 2024Recently, the formation of three-dimensional (3D) cell aggregates known as embryoid bodies (EBs) grown in media supplemented with HSC-specific morphogens has been...
Recently, the formation of three-dimensional (3D) cell aggregates known as embryoid bodies (EBs) grown in media supplemented with HSC-specific morphogens has been utilized for the directed differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), into clinically relevant hematopoietic stem cells (HSCs). However, delivering growth factors and nutrients have become ineffective in inducing synchronous differentiation of cells due to their 3D conformation. Moreover, irregularly sized EBs often lead to the formation of necrotic cores in larger EBs, impairing differentiation. Here, we developed two gelatin microparticles (GelMPs) with different release patterns and two HSC-related growth factors conjugated to them. Slow and fast releasing GelMPs were conjugated with bone morphogenic factor-4 (BMP-4) and stem cell factor (SCF), respectively. The sequential presentation of BMP-4 and SCF in GelMPs resulted in efficient and effective hematopoietic differentiation, shown by the enhanced gene and protein expression of several mesoderm and HSC-related markers, and the increased concentration of released HSC-related cytokines. In the present study, we were able to generate CD34, CD133, and FLT3 cells with similar cellular and molecular morphology as the naïve HSCs that can produce colony units of different blood cells, in vitro.
Topics: Bone Morphogenetic Protein 4; Cell Differentiation; Induced Pluripotent Stem Cells; Stem Cell Factor; Gelatin; Hematopoietic Stem Cells; Spheroids, Cellular; Animals; Humans; Mice
PubMed: 38844177
DOI: 10.1016/j.jconrel.2024.06.011 -
Genes & Development Jun 2024The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple...
The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike -null embryos, embryos containing hypomorphic mutations in lacking the ability to activate canonical downstream signals are still able to develop to birth but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of , leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identified processes regulating early mesoderm development by mechanisms involving both canonical and noncanonical pathways, including direct interaction with cell adhesion components and endocytic regulation.
Topics: Receptor, Fibroblast Growth Factor, Type 1; Animals; Mesoderm; Signal Transduction; Endocytosis; Gene Expression Regulation, Developmental; Mice; Embryonic Development; Protein Transport; Mutation
PubMed: 38834239
DOI: 10.1101/gad.351593.124