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BioRxiv : the Preprint Server For... May 2024Malocclusions are common craniofacial malformations which cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe...
Malocclusions are common craniofacial malformations which cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe skeletal malocclusion is invasive surgery. Developing improved therapeutic options requires a deeper understanding of the cellular mechanisms responsible for determining jaw bone length. We have recently shown that neural crest mesenchyme (NCM) can alter jaw length by controlling recruitment and function of mesoderm-derived osteoclasts. Transforming growth factor beta (TGF-β) signaling is critical to craniofacial development by directing bone resorption and formation, and heterozygous mutations in TGF-β type I receptor ( are associated with micrognathia in humans. To identify what role TGF-β signaling in NCM plays in controlling osteoclasts during mandibular development, mandibles of mouse embryos deficient in the gene encoding specifically in NCM were analyzed. Our lab and others have demonstrated that mice display significantly shorter mandibles with no condylar, coronoid, or angular processes. We hypothesize that TGF-β signaling in NCM can also direct later bone remodeling and further regulate late embryonic jaw bone length. Interestingly, analysis of mandibular bone through micro-computed tomography and Masson's trichrome revealed no significant difference in bone quality between the mice and controls, as measured by bone perimeter/bone area, trabecular rod-like diameter, number and separation, and gene expression of Collagen type 1 alpha 1 () and Matrix metalloproteinase 13 (). Though there was not a difference in localization of bone resorption within the mandible indicated by TRAP staining, mice had approximately three-fold less osteoclast number and perimeter than controls. Gene expression of receptor activator of nuclear factor kappa-β () and , markers of osteoclasts and their activity, also showed a three-fold decrease in mandibles. Evaluation of osteoblast-to-osteoclast signaling revealed no significant difference between mandibles and controls, leaving the specific mechanism unresolved. Finally, pharmacological inhibition of signaling during the initiation of bone mineralization and resorption significantly shortened jaw length in embryos. We conclude that TGF-β signaling in NCM decreases mesoderm-derived osteoclast number, that TGF-β signaling in NCM impacts jaw length late in development, and that this osteoblast-to-osteoclast communication may be occurring through an undescribed mechanism.
PubMed: 38826301
DOI: 10.1101/2024.05.24.595783 -
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 -
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 -
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