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International Journal of Molecular... May 2023Intestinal fibrosis, the most common complication of inflammatory bowel disease (IBD), is characterized by an uncontrolled deposition of extracellular matrix proteins...
Intestinal fibrosis, the most common complication of inflammatory bowel disease (IBD), is characterized by an uncontrolled deposition of extracellular matrix proteins leading to complications resolvable only with surgery. Transforming growth factor is the key player in the epithelial-mesenchymal transition (EMT) and fibrogenesis process, and some molecules modulating its activity, including peroxisome proliferator-activated receptor (PPAR)-γ and its agonists, exert a promising antifibrotic action. The purpose of this study is to evaluate the contribution of signaling other than EMT, such as the AGE/RAGE (advanced glycation end products/receptor of AGEs) and the senescence pathways, in the etiopathogenesis of IBD. We used human biopsies from control and IBD patients, and we used a mouse model of colitis induced by dextran-sodium-sulfate (DSS), without/with treatments with GED (PPAR-gamma-agonist), or 5-aminosalicylic acid (5-ASA), a reference drug for IBD treatment. In patients, we found an increase in EMT markers, AGE/RAGE, and senescence signaling activation compared to controls. Consistently, we found the overexpression of the same pathways in DSS-treated mice. Surprisingly, the GED reduced all the pro-fibrotic pathways, in some circumstances more efficiently than 5-ASA. Results suggest that IBD patients could benefit from a combined pharmacological treatment targeting simultaneously different pathways involved in pro-fibrotic signals. In this scenario, PPAR-gamma activation could be a suitable strategy to alleviate the signs and symptoms of IBD and also its progression.
Topics: Humans; Mice; Animals; PPAR gamma; Epithelial-Mesenchymal Transition; Colon; Colitis; Inflammatory Bowel Diseases; Epithelium; Dextran Sulfate; Mice, Inbred C57BL
PubMed: 37240299
DOI: 10.3390/ijms24108952 -
Annual Review of Physiology Feb 2021Embryonic definitive hematopoiesis generates hematopoietic stem and progenitor cells (HSPCs) essential for establishment and maintenance of the adult blood system. This... (Review)
Review
Embryonic definitive hematopoiesis generates hematopoietic stem and progenitor cells (HSPCs) essential for establishment and maintenance of the adult blood system. This process requires the specification of a subset of vascular endothelial cells to become blood-forming, or hemogenic, and the subsequent endothelial-to-hematopoietic transition to generate HSPCs therefrom. The mechanisms that regulate these processes are under intensive investigation, as their recapitulation in vitro from human pluripotent stem cells has the potential to generate autologous HSPCs for clinical applications. In this review, we provide an overview of hemogenic endothelial cell development and highlight the molecular events that govern hemogenic specification of vascular endothelial cells and the generation of multilineage HSPCs from hemogenic endothelium. We also discuss the impact of hemogenic endothelial cell development on adult hematopoiesis.
Topics: Animals; Cell Differentiation; Endothelial Cells; Endothelium, Vascular; Hemangioblasts; Hematopoiesis; Hematopoietic Stem Cells; Humans
PubMed: 33035429
DOI: 10.1146/annurev-physiol-021119-034352 -
Stem Cell Research & Therapy Oct 2023Peritoneal fibrosis (PF) is a pathophysiological condition caused by a variety of pathogenic factors. The most important features of PF are mesothelial-mesenchymal... (Review)
Review
Peritoneal fibrosis (PF) is a pathophysiological condition caused by a variety of pathogenic factors. The most important features of PF are mesothelial-mesenchymal transition and accumulation of activated (myo-)fibroblasts, which hinder effective treatment; thus, it is critical to identify other practical approaches. Recently, stem cell (SC) therapy has been indicated to be a potential strategy for this disease. Increasing evidence suggests that many kinds of SCs alleviate PF mainly by differentiating into mesothelial cells; secreting cytokines and extracellular vesicles; or modulating immune cells, particularly macrophages. However, there are relatively few articles summarizing research in this direction. In this review, we summarize the risk factors for PF and discuss the therapeutic roles of SCs from different sources. In addition, we outline effective approaches and potential mechanisms of SC therapy for PF. We hope that our review of articles in this area will provide further inspiration for research on the use of SCs in PF treatment.
Topics: Humans; Peritoneal Fibrosis; Epithelial-Mesenchymal Transition; Epithelium; Fibroblasts; Cell- and Tissue-Based Therapy; Peritoneum; Fibrosis
PubMed: 37817212
DOI: 10.1186/s13287-023-03520-3 -
Cells Sep 2022Despite many decades of research, complications of atherosclerosis resulting from the rupture or erosion of unstable plaques remain the leading cause of death worldwide.... (Review)
Review
Despite many decades of research, complications of atherosclerosis resulting from the rupture or erosion of unstable plaques remain the leading cause of death worldwide. Advances in cellular lineage tracing techniques have allowed researchers to begin investigating the role of individual cell types in the key processes regulating plaque stability, including maintenance of the fibrous cap, a protective collagen-rich structure that underlies the endothelium. This structure was previously thought to be entirely derived from smooth muscle cells (SMC), which migrated from the vessel wall. However, recent lineage tracing studies have identified endothelial cells (EC) as an essential component of this protective barrier through an endothelial-to-mesenchymal transition (EndoMT), a process that has previously been implicated in pulmonary, cardiac, and kidney fibrosis. Although the presence of EndoMT in atherosclerotic plaques has been shown by several laboratories using EC-lineage tracing mouse models, whether EndoMT is detrimental (i.e., worsening disease progression) or beneficial (i.e., an athero-protective response that prevents plaque instability) remains uncertain as there are data to support both possibilities, which will be further discussed in this review.
Topics: Animals; Atherosclerosis; Collagen; Endothelial Cells; Endothelium; Fibrosis; Mice; Plaque, Atherosclerotic
PubMed: 36230908
DOI: 10.3390/cells11192946 -
Cold Spring Harbor Perspectives in... May 2020Understanding how coronary blood vessels form and regenerate during development and progression of cardiac diseases will shed light on the development of new treatment... (Review)
Review
Understanding how coronary blood vessels form and regenerate during development and progression of cardiac diseases will shed light on the development of new treatment options targeting coronary artery diseases. Recent studies with the state-of-the-art technologies have identified novel origins of, as well as new, cellular and molecular mechanisms underlying the formation of coronary vessels in the postnatal heart, including collateral artery formation, endocardial-to-endothelial differentiation and mesenchymal-to-endothelial transition. These new mechanisms of coronary vessel formation and regeneration open up new possibilities targeting neovascularization for promoting cardiac repair and regeneration. Here, we highlight some recent studies on cellular mechanisms of coronary vessel formation, and discuss the potential impact and significance of the findings on basic research and clinical application for treating ischemic heart disease.
Topics: Animals; Cell Differentiation; Cell Lineage; Coronary Vessels; Endocardium; Endothelium; Heart; Heart Diseases; Humans; Myocardial Ischemia; Neovascularization, Physiologic; Organogenesis; Pericardium; Regeneration; Stem Cells
PubMed: 31636078
DOI: 10.1101/cshperspect.a037168 -
Current Atherosclerosis Reports Jun 2022In this review, we summarize current insights into the versatile roles of endothelial cells in atherogenesis. (Review)
Review
PURPOSE OF THE REVIEW
In this review, we summarize current insights into the versatile roles of endothelial cells in atherogenesis.
RECENT FINDINGS
The vascular endothelium represents the first barrier that prevents the entry of lipoproteins and leukocytes into the vessel wall, thereby controlling two key events in the pathogenesis of atherosclerosis. Disturbance of endothelial homeostasis increases vascular permeability, inflammation, and cellular trans-differentiation, which not only promotes the build-up of atherosclerotic plaques but is also involved in life-threatening thromboembolic complications such as plaque rupture and erosion. In this review, we focus on recent findings on endothelial lipoprotein transport, inflammation, cellular transitions, and barrier function. By using cutting-edge technologies such as single-cell sequencing, epigenetics, and cell fate mapping, novel regulatory mechanisms and endothelial cell phenotypes have been discovered, which have not only challenged established concepts of endothelial activation, but have also led to a different view of the disease.
Topics: Atherosclerosis; Endothelial Cells; Endothelium, Vascular; Humans; Inflammation; Plaque, Atherosclerotic
PubMed: 35404040
DOI: 10.1007/s11883-022-01023-9 -
Proceedings of the National Academy of... Aug 2023Ly6C monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6C monocytes have been shown to derive from Ly6C monocytes. NOTCH2...
Ly6C monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6C monocytes have been shown to derive from Ly6C monocytes. NOTCH2 signaling has been implicated as a trigger for Ly6C monocyte development, but the basis for this effect is unclear. Here, we examined the impact of NOTCH2 signaling of myeloid progenitors on the development of Ly6C monocytes in vitro. NOTCH2 signaling induced by delta-like ligand 1 (DLL1) efficiently induced the transition of Ly6C TREML4 monocytes into Ly6C TREML4 monocytes. We further identified two additional transcriptional requirements for development of Ly6C monocytes. Deletion of BCL6 from myeloid progenitors abrogated development of Ly6C monocytes. IRF2 was also required for Ly6C monocyte development in a cell-intrinsic manner. DLL1-induced in vitro transition into Ly6C TREML4 monocytes required IRF2 but unexpectedly could occur in the absence of NUR77 or BCL6. These results imply a transcriptional hierarchy for these factors in controlling Ly6C monocyte development.
Topics: Monocytes; Endothelium, Vascular; Hematopoiesis; Signal Transduction
PubMed: 37607223
DOI: 10.1073/pnas.2220853120 -
Biomolecules Dec 2021Formation of peritoneal adhesions (PA) is one of the major complications following intra-abdominal surgery. It is primarily caused by activation of the mesothelial layer... (Review)
Review
Formation of peritoneal adhesions (PA) is one of the major complications following intra-abdominal surgery. It is primarily caused by activation of the mesothelial layer and underlying tissues in the peritoneal membrane resulting in the transition of mesothelial cells (MCs) and fibroblasts to a pro-fibrotic phenotype. Pro-fibrotic transition of MCs-mesothelial-to-mesenchymal transition (MMT), and fibroblasts activation to myofibroblasts are interconnected to changes in cellular metabolism and culminate in the deposition of extracellular matrix (ECM) in the form of fibrotic tissue between injured sides in the abdominal cavity. However, ECM is not only a mechanical scaffold of the newly synthetized tissue but reciprocally affects fibrosis development. Hyaluronan (HA), an important component of ECM, is a non-sulfated glycosaminoglycan consisting of N-acetyl-D-glucosamine (GlcNAc) and D-glucuronic acid (GlcUA) that can affect the majority of processes involved in PA formation. This review considers the role of endogenously produced HA in the context of different fibrosis-related pathologies and its overlap in the development of PA.
Topics: Epithelium; Fibroblasts; Hyaluronic Acid; Myofibroblasts; Peritoneum
PubMed: 35053193
DOI: 10.3390/biom12010045 -
Stem Cells Translational Medicine Mar 2022The vascular wall is comprised of distinct layers controlling angiogenesis, blood flow, vessel anchorage within organs, and cell and molecule transit between blood and... (Review)
Review
The vascular wall is comprised of distinct layers controlling angiogenesis, blood flow, vessel anchorage within organs, and cell and molecule transit between blood and tissues. Moreover, some blood vessels are home to essential stem-like cells, a classic example being the existence in the embryo of hemogenic endothelial cells at the origin of definitive hematopoiesis. In recent years, microvascular pericytes and adventitial perivascular cells were observed to include multi-lineage progenitor cells involved not only in organ turnover and regeneration but also in pathologic remodeling, including fibrosis and atherosclerosis. These perivascular mesodermal elements were identified as native forerunners of mesenchymal stem cells. We have presented in this brief review our current knowledge on vessel wall-associated tissue remodeling cells with respect to discriminating phenotypes, functional diversity in health and disease, and potential therapeutic interest.
Topics: Endothelial Cells; Humans; Mesenchymal Stem Cells; Pericytes; Peripheral Blood Stem Cells; Stem Cells
PubMed: 35641167
DOI: 10.1093/stcltm/szab001 -
JCI Insight Jan 2024Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be...
Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13), which we verified by RNA in situ hybridization to be coexpressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in 3D culture. Our findings partially support historic speculations on the etiology of BPH and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.
Topics: Male; Adult; Humans; Aged; Prostatic Hyperplasia; Prostate; Epithelium; Fibroblasts; Gene Expression Profiling
PubMed: 37971878
DOI: 10.1172/jci.insight.176479