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Hepatology Communications May 2024HSCs, the resident pericytes of the liver, have consistently been at the forefront of liver research due to their crucial roles in various hepatic pathological... (Review)
Review
HSCs, the resident pericytes of the liver, have consistently been at the forefront of liver research due to their crucial roles in various hepatic pathological processes. Prior literature often depicted HSCs in a binary framework, categorizing them as either quiescent or activated. However, recent advances in HSC research, particularly the advent of single-cell RNA-sequencing, have revolutionized our understanding of these cells. This sophisticated technique offers an unparalleled, high-resolution insight into HSC populations, uncovering a spectrum of diversity and functional heterogeneity across various physiological states of the liver, ranging from liver development to the liver aging process. The single-cell RNA-sequencing revelations have also highlighted the intrinsic plasticity of HSCs and underscored their complex roles in a myriad of pathophysiological processes, including liver injury, repair, and carcinogenesis. This review aims to integrate and clarify these recent discoveries, focusing on how the inherent plasticity of HSCs is central to their dynamic roles both in maintaining liver homeostasis and orchestrating responses to liver injury. Future research will clarify whether findings from rodent models can be translated to human livers and guide how these insights are harnessed to develop targeted therapeutic interventions.
Topics: Humans; Hepatic Stellate Cells; Liver; Carcinogenesis; Homeostasis; RNA
PubMed: 38619452
DOI: 10.1097/HC9.0000000000000411 -
Journal of Dental Sciences Apr 2024Dental pulp stem cells (DPSCs) exhibit versatile differentiation capabilities, including neural differentiation, prompting the hypothesis that they may be implicated in...
BACKGROUND/PURPOSE
Dental pulp stem cells (DPSCs) exhibit versatile differentiation capabilities, including neural differentiation, prompting the hypothesis that they may be implicated in the neurodevelopment of teeth. This study aimed to explore the temporospatial dynamics between DPSCs and tooth innervation, employing immunofluorescence staining and fluorescent dye injections to investigate the distribution of DPSCs, neural stem cells (NSCs), nerve growth cones, and sensory nerves in developing mouse tooth germs at various stages.
MATERIALS AND METHODS
Immunofluorescence staining targeting CD146, Nestin, and GAP-43, along with the injection of AM1-43 fluorescent dye, were utilized to observe the distribution of DPSCs, NSCs, nerve growth cones, and sensory nerves in mouse tooth germs at different developmental stages.
RESULTS
Positive CD146 immunostaining was observed in microvascular endothelial cells and pericytes within and around the tooth germ. The percentage of CD146-positive cells remained consistent between 4-day-old and 8-day-old second molar tooth germs. Conversely, Nestin expression in odontoblasts and their processes decreased in 8-day-old tooth germs compared to 4-day-old ones. Positive immunostaining for GAP-43 and AM1-43 fluorescence revealed the entry of nerve growth cones and sensory nerves into the pulp in 8-day-old tooth germs, while these elements were confined to the dental follicle in 4-day-old germs. No co-localization of CD146-positive DPSCs with nerve growth cones and sensory nerves was observed.
CONCLUSION
DPSCs and NSCs were present in dental pulp tissue before nerves penetrated the pulp. The decline in NSCs after nerve entry suggests a potential role for DPSCs and NSCs in attracting neural growth and/or differentiation within the pulp.
PubMed: 38618089
DOI: 10.1016/j.jds.2024.02.007 -
International Journal of Molecular... Apr 2024Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory... (Review)
Review
Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.
Topics: Female; Humans; Pregnancy; Insulin; Diabetes, Gestational; Communication; Pancreas; Insulin, Regular, Human; Islets of Langerhans
PubMed: 38612880
DOI: 10.3390/ijms25074070 -
International Journal of Molecular... Mar 2024Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most... (Review)
Review
Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is enriched in the cerebral vasculature and has diverse roles in metabolic balance, mitochondrial stabilization, redox balance, and anti-inflammation. In this review, we first briefly introduce cerebrovascular aging in VCID and the NRF2 pathway. We then extensively discuss the effects of NRF2 activation in cerebrovascular components such as endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. Finally, we summarize the clinical potential of NRF2 activators in VCID.
Topics: Humans; Endothelial Cells; NF-E2-Related Factor 2; Cognitive Dysfunction; Dementia, Vascular
PubMed: 38612642
DOI: 10.3390/ijms25073833 -
Diabetes Jul 2024The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate...
The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in DR and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study showed both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2 inhibitors may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.
Topics: Animals; Diabetic Retinopathy; Sodium-Glucose Transporter 2 Inhibitors; Mice; Microglia; Diabetes Mellitus, Experimental; Male; Vascular Endothelial Growth Factor A; Retina; Mice, Inbred C57BL; Retinal Vessels; Thiophenes; Angiopoietin-2
PubMed: 38608284
DOI: 10.2337/db22-0970 -
Nature Communications Apr 2024Formation of organo-typical vascular networks requires cross-talk between differentiating parenchymal cells and developing blood vessels. Here we identify a Vegfa driven...
Formation of organo-typical vascular networks requires cross-talk between differentiating parenchymal cells and developing blood vessels. Here we identify a Vegfa driven venous sprouting process involving parenchymal to vein cross-talk regulating venous endothelial Vegfa signaling strength and subsequent formation of a specialized angiogenic cell, prefabricated with an intact lumen and pericyte coverage, termed L-Tip cell. L-Tip cell selection in the venous domain requires genetic interaction between vascular Aplnra and Kdrl in a subset of venous endothelial cells and exposure to parenchymal derived Vegfa and Apelin. Parenchymal Esm1 controls the spatial positioning of venous sprouting by fine-tuning local Vegfa availability. These findings may provide a conceptual framework for understanding how Vegfa generates organo-typical vascular networks based on the selection of competent endothelial cells, induced via spatio-temporal control of endothelial Kdrl signaling strength involving multiple parenchymal derived cues generated in a tissue dependent metabolic context.
Topics: Angiogenesis; Endothelial Cells; Neovascularization, Physiologic; Veins
PubMed: 38600061
DOI: 10.1038/s41467-024-47434-x -
Biomaterials and Biosystems Jun 2024Spatial cell organization and biofabrication of microcapillary networks in vitro has a great potential in tissue engineering and regenerative medicine. This study...
Spatial cell organization and biofabrication of microcapillary networks in vitro has a great potential in tissue engineering and regenerative medicine. This study explores the impact of local cell density enhancement achieved through an innovative sound-based patterning on microcapillary networks formation and their proteomic profile. Human umbilical vein endothelial cells (HUVEC) and human pericytes from placenta (hPC-PL) were mixed in a fibrin suspension. The mild effect of sound-induced hydrodynamic forces condensed cells into architected geometries showing good fidelity to the numerical simulation of the physical process. Local cell density increased significantly within the patterned areas and the capillary-like structures formed following the cell density gradient. Over five days, these patterns were well-maintained, resulting in concentric circles and honeycomb-like structures. Proteomic analysis of the pre-condensed cells cultured for 5 days, revealed over 900 differentially expressed proteins when cells were preassembled through mild-hydrodynamic forces. Gene ontology (GO) enrichment analysis identified cellular components, molecular functions, and biological processes that were up- and down-regulated, providing insights regarding molecular processes influenced by the local density enhancement. Furthermore, we employed Ingenuity Pathway Analysis (IPA) to identify altered pathways and predict upstream regulators. Notably, VEGF-A emerged as one of the most prominent upstream regulators. Accordingly, this study initiates the unraveling of the changes in microcapillary networks at both molecular and proteins level induced by cell condensation obtained through sound patterning. The findings provide valuable insights for further investigation into sound patterning as a biofabrication technique for creating more complex microcapillary networks and advancing in vitro models.
PubMed: 38596510
DOI: 10.1016/j.bbiosy.2024.100094 -
IScience Apr 2024Diabetic neuropathy (DN) is a major complication of . Chondroitin sulfate (CS) is one of the most important extracellular matrix components and is known to interact with...
Diabetic neuropathy (DN) is a major complication of . Chondroitin sulfate (CS) is one of the most important extracellular matrix components and is known to interact with various diffusible factors; however, its role in DN pathology has not been examined. Therefore, we generated CSGalNAc-T1 knockout (T1KO) mice, in which CS levels were reduced. We demonstrated that diabetic T1KO mice were much more resistant to DN than diabetic wild-type (WT) mice. We also found that interactions between pericytes and vascular endothelial cells were more stable in T1KO mice. Among the RNA-seq results, we focused on the transforming growth factor β signaling pathway and found that the phosphorylation of Smad2/3 was less upregulated in T1KO mice than in WT mice under hyperglycemic conditions. Taken together, a reduction in CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis.
PubMed: 38595797
DOI: 10.1016/j.isci.2024.109528 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Apr 2024To delve deeply into the dynamic trajectories of cell subpopulations and the communication network among immune cell subgroups during the malignant progression of...
OBJECTIVE
To delve deeply into the dynamic trajectories of cell subpopulations and the communication network among immune cell subgroups during the malignant progression of glioblastoma (GBM), and to endeavor to unearth key risk biomarkers in the GBM malignancy progression, so as to provide a more profound understanding for the treatment and prognosis of this disease by integrating transcriptomic data and clinical information of the GBM patients.
METHODS
Utilizing single-cell sequencing data analysis, we constructed a cell subgroup atlas during the malignant progression of GBM. The Monocle2 tool was employed to build dynamic progression trajectories of the tumor cell subgroups in GBM. Through gene enrichment analysis, we explored the biological processes enriched in genes that significantly changed with the malignancy progression of GBM tumor cell subpopulations. CellChat was used to identify the communication network between the different immune cell subgroups. Survival analysis helped in identifying risk molecular markers that impacted the patient prognosis during the malignant progression of GBM. This method ological approach offered a comprehensive and detailed examination of the cellular and molecular dynamics within GBM, providing a robust framework for understanding the disease' s progression and potential therapeutic targets.
RESULTS
The analysis of single-cell sequencing data identified 6 different cell types, including lymphocytes, pericytes, oligodendrocytes, macrophages, glioma cells, and microglia. The 27 151 cells in the single-cell dataset included 3 881 cells from the patients with low-grade glioma (LGG), 10 166 cells from the patients with newly diagnosed GBM, and 13 104 cells from the patients with recurrent glioma (rGBM). The pseudo-time analysis of the glioma cell subgroups indicated significant cellular heterogeneity during malignant progression. The cell interaction analysis of immune cell subgroups revealed the communication network among the different immune subgroups in GBM malignancy, identifying 22 biologically significant ligand-receptor pairs across 12 key biological pathways. Survival analysis had identified 8 genes related to the prognosis of the GBM patients, among which , , , , , , and were high-risk genes in the GBM patients, and was low-risk genes in the GBM patients. These findings not only provided new theoretical bases for the treatment of GBM, but also offered fresh insights for the prognosis assessment and treatment decision-making for the GBM patients.
CONCLUSION
This research comprehensively and profoundly reveals the dynamic changes in glioma cell subpopulations and the communication patterns among the immune cell subgroups during the malignant progression of GBM. These findings are of significant importance for understanding the complex biological processes of GBM, providing crucial new insights for precision medicine and treatment decisions in GBM. Through these studies, we hope to provide more effective treatment options and more accurate prognostic assessments for the patients with GBM.
Topics: Humans; Glioblastoma; Brain Neoplasms; Neoplasm Recurrence, Local; Glioma; Prognosis; Cell Communication; Carboxypeptidases; Repressor Proteins
PubMed: 38595234
DOI: 10.19723/j.issn.1671-167X.2024.02.001 -
EMBO Molecular Medicine May 2024Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis....
Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis. Transcriptional regulators that control the reprogramming of EC into TEC are poorly understood. We identified Forkhead box F1 (FOXF1) as a critical regulator of EC-to-TEC transition. FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific overexpression of FOXF1 normalized tumor vessels and inhibited the progression of lung cancer. FOXF1 deficiency decreased Wnt/β-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/β-catenin signaling in TECs, normalized tumor vessels and inhibited the progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/β-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC.
Topics: Animals; Frizzled Receptors; Forkhead Transcription Factors; Lung Neoplasms; Humans; Mice; Endothelial Cells; Carcinoma, Non-Small-Cell Lung; Wnt Signaling Pathway; Disease Progression; Neovascularization, Pathologic
PubMed: 38589650
DOI: 10.1038/s44321-024-00064-8