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International Journal of Molecular... Sep 2023represents a type of single-transmembrane adaptor protein containing an N-terminal cysteine-rich domain and a proline-rich C-terminal region. Nine subfamily genes have...
represents a type of single-transmembrane adaptor protein containing an N-terminal cysteine-rich domain and a proline-rich C-terminal region. Nine subfamily genes have been proposed in most vertebrates; however, some might be species-specific. The number of genes present in zebrafish remains unclear. This study aimed to investigate the evolutionary relationships among family genes in zebrafish (TU strain) using phylogenetic and syntenic analyses. The function of was preliminarily examined via CRISPR/Cas13d-mediated knockdown. Following identification in zebrafish, 10 family genes, namely , , , , , , , , , and , were classified into three main clades and six subclades. Their encoding proteins contained a cysteine-rich N-terminal domain and a proline-rich C-terminal region containing different motifs. A specific syntenic block containing and was observed to be conserved across all species. Furthermore, all these genes were expressed during embryogenesis. was expressed in the presomitic mesoderm, somites, and so on. was identified as a regulator of the expression of the somite formation marker . Overall, our study provides new insights into the evolution of family genes and the control of over the convergent extension cells of somitic precursors in zebrafish.
Topics: Animals; Zebrafish; Zebrafish Proteins; Phylogeny; Cysteine; Membrane Proteins; Proline; Gene Expression Regulation, Developmental
PubMed: 37762365
DOI: 10.3390/ijms241814062 -
Frontiers in Bioscience (Landmark... Apr 2024Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by aberrant amyloid precursor protein (APP) cleavage, pathological... (Review)
Review
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by aberrant amyloid precursor protein (APP) cleavage, pathological aggregations of beta-amyloid (Aβ) that make up Aβ plaques and hyperphosphorylation of Tau that makes up neurofibrillary tangles (NFTs). Although progress has been made in research on AD, the fundamental causes of this disease have not been fully elucidated. Recent studies have shown that vascular dysfunction especially the loss of pericytes plays a significant role in the onset of AD. Pericytes play a variety of important roles in the nervous system including the regulation of the cerebral blood flow (CBF), the formation and maintenance of the blood-brain barrier (BBB), angiogenesis, and the clearance of toxic substances from the brain. Pericytes participate in the transport of Aβ through various receptors, and Aβ acts on pericytes to cause them to constrict, detach, and die. The loss of pericytes elevates the levels of Aβ1-40 and Aβ1-42 by disrupting the integrity of the BBB and reducing the clearance of soluble Aβ from the brain interstitial fluid. The aggravated deposition of Aβ further exacerbates pericyte dysfunction, forming a vicious cycle. The combined influence of these factors eventually results in the loss of neurons and cognitive decline. Further exploration of the interactions between pericytes and Aβ is beneficial for understanding AD and could lead to the identification of new therapeutic targets for the prevention and treatment of AD. In this review, we explore the characterization of pericytes, interactions between pericytes and other cells in the neurovascular unit (NVU), and the physiological functions of pericytes and dysfunctions in AD. This review discusses the interactions between pericytes and Aβ, as well as current and further strategies for preventing or treating AD targeting pericytes.
Topics: Pericytes; Alzheimer Disease; Humans; Amyloid beta-Peptides; Blood-Brain Barrier; Animals; Brain
PubMed: 38682184
DOI: 10.31083/j.fbl2904136 -
IScience Nov 2023Long non-coding RNAs (lncRNAs) play widespread roles in various processes. However, there is still limited understanding of the precise mechanisms through which they...
Long non-coding RNAs (lncRNAs) play widespread roles in various processes. However, there is still limited understanding of the precise mechanisms through which they regulate early stage cardiomyocyte differentiation. In this study, we identified a specific lncRNA called , which is transcribed from a bidirectional promoter of LIM Homeobox 1 (LHX1) gene. Our findings demonstrated that is nuclear-localized and transiently elevated expression along with LHX1 during early differentiation of cardiomyocytes. The phenotype was rescued by overexpression of LHX1 into the hESCs, indicating LHX1 is the downstream of . Mechanistically, we discovered that physically interacted with RNA/histone-binding protein PHF6 during mesoderm commitment and efficiently replaced conventional histone H2A with a histone variant H2A.Z at the promoter region of LHX1. In summary, our work uncovers a novel lncRNA, , which plays a vital role in mediating the exchange of histone variants H2A.Z and H2A at the promoter region of LHX1.
PubMed: 37942009
DOI: 10.1016/j.isci.2023.108051 -
Cell Reports Aug 2023Pancreatic islets are endocrine organs that depend on their microvasculature to function. Along with endothelial cells, pericytes comprise the islet microvascular...
Pancreatic islets are endocrine organs that depend on their microvasculature to function. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here, we investigate islet pericyte density, phenotype, and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (GADA+), and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes toward myofibroblasts. Using publicly available RNA sequencing (RNA-seq) data, we further found that transcriptional alterations related to endothelin-1 signaling and vascular and extracellular matrix (ECM) remodeling are hallmarks of single autoantibody (Aab)+ donor pancreata. Our data show that microvascular dysfunction is present at early stages of islet autoimmunity.
Topics: Humans; Diabetes Mellitus, Type 1; Pericytes; Endothelial Cells; Islets of Langerhans; Autoantibodies
PubMed: 37531253
DOI: 10.1016/j.celrep.2023.112913 -
JCI Insight Jul 2023Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multisystem disease. The wide range of manifestations...
Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multisystem disease. The wide range of manifestations observed in patients with mitochondrial disease results from varying fractions of abnormal mtDNA molecules in different cells and tissues, a phenomenon termed heteroplasmy. However, the landscape of heteroplasmy across cell types within tissues and its influence on phenotype expression in affected patients remains largely unexplored. Here, we identify nonrandom distribution of a pathogenic mtDNA variant across a complex tissue using single-cell RNA-Seq, mitochondrial single-cell ATAC sequencing, and multimodal single-cell sequencing. We profiled the transcriptome, chromatin accessibility state, and heteroplasmy in cells from the eyes of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and from healthy control donors. Utilizing the retina as a model for complex multilineage tissues, we found that the proportion of the pathogenic m.3243A>G allele was neither evenly nor randomly distributed across diverse cell types. All neuroectoderm-derived neural cells exhibited a high percentage of the mutant variant. However, a subset of mesoderm-derived lineage, namely the vasculature of the choroid, was near homoplasmic for the WT allele. Gene expression and chromatin accessibility profiles of cell types with high and low proportions of m.3243A>G implicate mTOR signaling in the cellular response to heteroplasmy. We further found by multimodal single-cell sequencing of retinal pigment epithelial cells that a high proportion of the pathogenic mtDNA variant was associated with transcriptionally and morphologically abnormal cells. Together, these findings show the nonrandom nature of mitochondrial variant partitioning in human mitochondrial disease and underscore its implications for mitochondrial disease pathogenesis and treatment.
Topics: Humans; Heteroplasmy; MELAS Syndrome; Mitochondrial Diseases; DNA, Mitochondrial; Retina; Retinal Diseases; Chromatin
PubMed: 37289546
DOI: 10.1172/jci.insight.165937 -
International Journal of Molecular... Jul 2023Scar formation during normal tissue regeneration in adults may result in noticeable cosmetic and functional defects and have a significant impact on the quality of life.... (Review)
Review
Scar formation during normal tissue regeneration in adults may result in noticeable cosmetic and functional defects and have a significant impact on the quality of life. In contrast, fetal tissues in the mid-gestation period are known to be capable of complete regeneration with the restitution of the initial architecture, organization, and functional activity. Successful treatments that are targeted to minimize scarring can be realized by understanding the cellular and molecular mechanisms of fetal wound regeneration. However, such experiments are limited by the inaccessibility of fetal material for comparable studies. For this reason, the molecular mechanisms of fetal regeneration remain unknown. Mesenchymal stromal cells (MSCs) are central to tissue repair because the molecules they secrete are involved in the regulation of inflammation, angiogenesis, and remodeling of the extracellular matrix. The mesodermal differentiation of human pluripotent stem cells (hPSCs) recapitulates the sequential steps of embryogenesis in vitro and provides the opportunity to generate the isogenic cell models of MSCs corresponding to different stages of human development. Further investigation of the functional activity of cells from stromal differon in a pro-inflammatory microenvironment will procure the molecular tools to better understand the fundamental mechanisms of fetal tissue regeneration. Herein, we review recent advances in the generation of clonal precursors of primitive mesoderm cells and MSCs from hPSCs and discuss critical factors that determine the functional activity of MSCs-like cells in a pro-inflammatory microenvironment in order to identify therapeutic targets for minimizing scarring.
Topics: Adult; Humans; Cicatrix; Quality of Life; Wound Healing; Mesoderm; Pluripotent Stem Cells
PubMed: 37569321
DOI: 10.3390/ijms241511945 -
Development (Cambridge, England) Dec 2023De novo variants affecting monoubiquitylation of histone H2B (H2Bub1) are enriched in human congenital heart disease. H2Bub1 is required in stem cell differentiation,...
De novo variants affecting monoubiquitylation of histone H2B (H2Bub1) are enriched in human congenital heart disease. H2Bub1 is required in stem cell differentiation, cilia function, post-natal cardiomyocyte maturation and transcriptional elongation. However, how H2Bub1 affects cardiogenesis is unknown. We show that the H2Bub1-deposition complex (RNF20-RNF40-UBE2B) is required for mouse cardiogenesis and for differentiation of human iPSCs into cardiomyocytes. Mice with cardiac-specific Rnf20 deletion are embryonic lethal and have abnormal myocardium. We then analyzed H2Bub1 marks during differentiation of human iPSCs into cardiomyocytes. H2Bub1 is erased from most genes at the transition from cardiac mesoderm to cardiac progenitor cells but is preserved on a subset of long cardiac-specific genes. When H2Bub1 is reduced in iPSC-derived cardiomyocytes, long cardiac-specific genes have fewer full-length transcripts. This correlates with H2Bub1 accumulation near the center of these genes. H2Bub1 accumulation near the center of tissue-specific genes was also observed in embryonic fibroblasts and fetal osteoblasts. In summary, we show that normal H2Bub1 distribution is required for cardiogenesis and cardiomyocyte differentiation, and suggest that H2Bub1 regulates tissue-specific gene expression by increasing the amount of full-length transcripts.
Topics: Animals; Humans; Mice; Heart; Heart Defects, Congenital; Histones; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 38038666
DOI: 10.1242/dev.201899 -
Frontiers in Endocrinology 2023Diabetic retinopathy (DR) is a prevalent complication of diabetes, significantly impacting patients' quality of life due to vision loss. No pharmacological therapies are... (Review)
Review
Diabetic retinopathy (DR) is a prevalent complication of diabetes, significantly impacting patients' quality of life due to vision loss. No pharmacological therapies are currently approved for DR, excepted the drugs to treat diabetic macular edema such as the anti-VEGF agents or steroids administered by intraocular route. Advancements in research have highlighted the crucial role of early intervention in DR for halting or delaying disease progression. This holds immense significance in enhancing patients' quality of life and alleviating the societal burden associated with medical care costs. The non-proliferative stage represents the early phase of DR. In comparison to the proliferative stage, pathological changes primarily manifest as microangiomas and hemorrhages, while at the cellular level, there is a loss of pericytes, neuronal cell death, and disruption of components and functionality within the retinal neuronal vascular unit encompassing pericytes and neurons. Both neurodegenerative and microvascular abnormalities manifest in the early stages of DR. Therefore, our focus lies on the non-proliferative stage of DR and we have initially summarized the mechanisms involved in its development, including pathways such as polyols, that revolve around the pathological changes occurring during this early stage. We also integrate cutting-edge mechanisms, including leukocyte adhesion, neutrophil extracellular traps, multiple RNA regulation, microorganisms, cell death (ferroptosis and pyroptosis), and other related mechanisms. The current status of drug therapy for early-stage DR is also discussed to provide insights for the development of pharmaceutical interventions targeting the early treatment of DR.
Topics: Humans; Diabetic Retinopathy; Quality of Life; Macular Edema; Neurons; Pericytes; Diabetes Mellitus
PubMed: 38027131
DOI: 10.3389/fendo.2023.1270145 -
Theranostics 2024Endosialin, also known as tumor endothelial marker 1 (TEM1) or CD248, is a single transmembrane glycoprotein with a C-type lectin-like domain. Endosialin is mainly... (Review)
Review
Endosialin, also known as tumor endothelial marker 1 (TEM1) or CD248, is a single transmembrane glycoprotein with a C-type lectin-like domain. Endosialin is mainly expressed in the stroma, especially in cancer-associated fibroblasts and pericytes, in most solid tumors. Endosialin is also expressed in tumor cells of most sarcomas. Endosialin can promote tumor progression through different mechanisms, such as promoting tumor cell proliferation, adhesion and migration, stimulating tumor angiogenesis, and inducing an immunosuppressive tumor microenvironment. Thus, it is considered an ideal target for cancer treatment. Several endosialin-targeted antibodies and therapeutic strategies have been developed and have shown preliminary antitumor effects. Here, we reviewed the endosialin expression pattern in different cancer types, discussed the mechanisms by which endosialin promotes tumor progression, and summarized current therapeutic strategies targeting endosialin.
Topics: Humans; Antigens, Neoplasm; Neoplasms; Neovascularization, Pathologic; Pericytes; Tumor Microenvironment; Antigens, CD
PubMed: 38164138
DOI: 10.7150/thno.89495 -
Glia Aug 2023Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia...
Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood-brain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX CR1 mice, and in the human frontal cortex. Using in vivo two-photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.
Topics: Mice; Humans; Animals; Pericytes; Mice, Transgenic; Microglia; Brain; Blood-Brain Barrier; Alzheimer Disease
PubMed: 36994950
DOI: 10.1002/glia.24371