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Journal of Dental Research Jul 2024A ligature-induced periodontitis model was established in wild-type and CD146; Rosa mice to explore the function of pericytes in alveolar bone formation. We found that...
A ligature-induced periodontitis model was established in wild-type and CD146; Rosa mice to explore the function of pericytes in alveolar bone formation. We found that during periodontitis progression and periodontal wound healing, CD146/NG2 pericytes were enriched in the periodontal tissue areas, which could migrate to the alveolar bone surface and colocalize with ALP/OCN osteoblasts. Chemokine C-X-C motif receptor 4 (CXCR4) inhibition using AMD3100 blocked CD146-Cre pericyte migration and osteogenesis, as well as further exacerbated periodontitis-associated bone loss. Next, primary pericytes were sorted out by magnetic-activated cell sorting and demonstrated that C-X-C motif chemokine ligand 12 (CXCL12) promotes pericyte migration and osteogenesis via CXCL12-CXCR4-Rac1 signaling. Finally, the local administration of an adeno-associated virus for Rac1 overexpression in NG2 pericytes promotes osteoblast differentiation of pericytes and increases alveolar bone volume in periodontitis. Thus, our results provided the evidence that pericytes may migrate and osteogenesis via the CXCL12-CXCR4-Rac1 axis during the pathological process of periodontitis.
Topics: Pericytes; Animals; Osteogenesis; Periodontitis; Cell Movement; Mice; Chemokine CXCL12; Receptors, CXCR4; Alveolar Bone Loss; Signal Transduction; rac1 GTP-Binding Protein; Disease Models, Animal; CD146 Antigen; Osteoblasts; Cell Differentiation; Cyclams; Benzylamines
PubMed: 38822570
DOI: 10.1177/00220345241244687 -
Development (Cambridge, England) Jun 2024Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral to calvarial growth and enclosure of the brain. The...
Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral to calvarial growth and enclosure of the brain. The cellular behaviors and signals underlying the morphogenetic process of calvarial expansion are unknown. Time-lapse light-sheet imaging of mouse embryos revealed calvarial progenitors intercalate in 3D in the CM above the eye, and exhibit protrusive and crawling activity more apically. CM cells express non-canonical Wnt/planar cell polarity (PCP) core components and calvarial osteoblasts are bidirectionally polarized. We found non-canonical ligand Wnt5a-/- mutants have less dynamic cell rearrangements and protrusive activity. Loss of CM-restricted Wntless (CM-Wls), a gene required for secretion of all Wnt ligands, led to diminished apical expansion of Osx+ calvarial osteoblasts in the frontal bone primordia in a non-cell autonomous manner without perturbing proliferation or survival. Calvarial osteoblast polarization, progressive cell elongation and enrichment for actin along the baso-apical axis were dependent on CM-Wnts. Thus, CM-Wnts regulate cellular behaviors during calvarial morphogenesis for efficient apical expansion of calvarial osteoblasts. These findings also offer potential insights into the etiologies of calvarial dysplasias.
Topics: Animals; Osteoblasts; Skull; Mice; Mesoderm; Morphogenesis; Wnt Proteins; Cell Polarity; Wnt-5a Protein; Cell Movement; Cell Proliferation
PubMed: 38814743
DOI: 10.1242/dev.202596 -
Nature Communications May 2024The emergence of new structures can often be linked to the evolution of novel cell types that follows the rewiring of developmental gene regulatory subnetworks....
The emergence of new structures can often be linked to the evolution of novel cell types that follows the rewiring of developmental gene regulatory subnetworks. Vertebrates are characterized by a complex body plan compared to the other chordate clades and the question remains of whether and how the emergence of vertebrate morphological innovations can be related to the appearance of new embryonic cell populations. We previously proposed, by studying mesoderm development in the cephalochordate amphioxus, a scenario for the evolution of the vertebrate head mesoderm. To further test this scenario at the cell population level, we used scRNA-seq to construct a cell atlas of the amphioxus neurula, stage at which the main mesodermal compartments are specified. Our data allowed us to validate the presence of a prechordal-plate like territory in amphioxus. Additionally, the transcriptomic profile of somite cell populations supports the homology between specific territories of amphioxus somites and vertebrate cranial/pharyngeal and lateral plate mesoderm. Finally, our work provides evidence that the appearance of the specific mesodermal structures of the vertebrate head was associated to both segregation of pre-existing cell populations, and co-option of new genes for the control of myogenesis.
Topics: Animals; Mesoderm; Lancelets; Head; Gene Expression Regulation, Developmental; Vertebrates; Somites; Biological Evolution; Transcriptome
PubMed: 38811547
DOI: 10.1038/s41467-024-48774-4 -
Stem Cell Research Aug 2024The SORD neuropathy has been identified as the most common autosomal recessive inherited neuropathy, occurring in thousands of patients worldwide. Fibroblast lines from...
The SORD neuropathy has been identified as the most common autosomal recessive inherited neuropathy, occurring in thousands of patients worldwide. Fibroblast lines from 3 different patients containing the c.753delG; p.Ala253GlnfsTer27 SORD mutations were reprogrammed into induced Pluripotent Stem Cell (iPSC) lines. These iPSC lines demonstrate an apparent normal karyotype and have positive expression of pluripotency markers. These iPSC lines also stain positively for Ectoderm, Endoderm and Mesoderm markers following Embryoid body differentiation. These lines pose to serve as a valuable disease modeling resource for studying the SORD neuropathy, including studying disease phenotype and treatment efficacy.
Topics: Induced Pluripotent Stem Cells; Humans; Mutation; Cell Line; Cell Differentiation; Male; Female
PubMed: 38796985
DOI: 10.1016/j.scr.2024.103449 -
Viruses May 2024SARS-CoV-2 primarily infects the lungs via the ACE2 receptor but also other organs including the kidneys, the gastrointestinal tract, the heart, and the skin. SARS-CoV-2...
SARS-CoV-2 primarily infects the lungs via the ACE2 receptor but also other organs including the kidneys, the gastrointestinal tract, the heart, and the skin. SARS-CoV-2 also infects the brain, but the hematogenous route of viral entry to the brain is still not fully characterized. Understanding how SARS-CoV-2 traverses the blood-brain barrier (BBB) as well as how it affects the molecular functions of the BBB are unclear. In this study, we investigated the roles of the receptors ACE2 and DPP4 in the SARS-CoV-2 infection of the discrete cellular components of a transwell BBB model comprising HUVECs, astrocytes, and pericytes. Our results demonstrate that direct infection on the BBB model does not modulate paracellular permeability. Also, our results show that SARS-CoV-2 utilizes clathrin and caveolin-mediated endocytosis to traverse the BBB, resulting in the direct infection of the brain side of the BBB model with a minimal endothelial infection. In conclusion, the BBB is susceptible to SARS-CoV-2 infection in multiple ways, including the direct infection of endothelium, astrocytes, and pericytes involving ACE2 and/or DPP4 and the blood-to-brain transcytosis, which is an event that does not require the presence of host receptors.
Topics: Blood-Brain Barrier; Humans; SARS-CoV-2; Transcytosis; Angiotensin-Converting Enzyme 2; Pericytes; COVID-19; Virus Internalization; Astrocytes; Dipeptidyl Peptidase 4; Brain; Endocytosis; Human Umbilical Vein Endothelial Cells; Permeability
PubMed: 38793666
DOI: 10.3390/v16050785 -
International Journal of Molecular... May 2024Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This... (Review)
Review
Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system.
Topics: Pericytes; Humans; Tumor Microenvironment; Animals; Brain Neoplasms; Glioma; Glioblastoma; Disease Progression; Tumor-Associated Macrophages
PubMed: 38791110
DOI: 10.3390/ijms25105072 -
Cureus Apr 2024Endoscopic third ventriculocysternostomy (ETV) is a minimally invasive neurosurgical technique with good results in the treatment of obstructive hydrocephalus. The...
Endoscopic Ventriculocysternostomy, Magendie Foraminoplasty, and Plexusectomy With Craniovertebral Shunt Placement in a Pediatric Patient With Hydrocephalus and VACTERL Association: A Novel Treatment Option.
Endoscopic third ventriculocysternostomy (ETV) is a minimally invasive neurosurgical technique with good results in the treatment of obstructive hydrocephalus. The VACTERL (vertebrae, anorectal, cardiovascular, tracheal, esophageal, renal, limb defects) association, or VATER syndrome, is defined as congenital malformations, mostly derived from the mesoderm, affecting specific areas. It is diagnosed by the presence of at least three of the seven characteristic malformations that describe it. The association of this pathology and obstructive hydrocephalus in pediatric age is not common, making management and conventional neurosurgical procedures difficult due to the number of underlying pathologies. In this study, we report the management of hydrocephalus and VACTERL association with multiple congenital malformations in a 30-day-old premature neonate (birth at 29 weeks). Operations performed prior to admission to our service included: coloesophagoplasty and placement of esophagostoma in the left anterior cervical region, perineal anorectoplasty, gastrostomy and placement of sigmoidostomy in the left anterior abdominal wall, relaparotomy, gastric suture, sanitation, and abdominal drainage. Upon admission, the patient showed a Grade 3 intraventricular hemorrhage and internal occlusive hydrocephalus due to circulatory blockage of the cerebrospinal fluid (CSF) at the level of the outlet of the fourth ventricle. This was accompanied by intracranial hypertension and refractory cervical syringomyelia. We performed endoscopic ventriculocysternostomy plus plexusectomy plus Magendie foraminoplasty with craniovertebral shunt placement, achieving excellent results after two interventions. This is the first case described in the literature placing a craniovertebral shunt using a lateral-ventricle-to-the-subarachnoid-spinal-space-stenting technique in a patient with VACTERL association, which represents an innovation in the field of minimally invasive pediatric neurosurgery.
PubMed: 38784296
DOI: 10.7759/cureus.58845 -
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