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ELife Jul 2023Expression of activated Ras, Ras, provides cultured cells with a proliferation and survival advantage that simplifies the generation of continuous cell lines. Here, we...
Expression of activated Ras, Ras, provides cultured cells with a proliferation and survival advantage that simplifies the generation of continuous cell lines. Here, we used lineage-restricted Ras expression to generate continuous cell lines of muscle, glial, and epithelial cell type. Additionally, cell lines with neuronal and hemocyte characteristics were isolated by cloning from cell cultures established with broad Ras expression. Differentiation with the hormone ecdysone caused maturation of cells from mesoderm lines into active muscle tissue and enhanced dendritic features in neuronal-like lines. Transcriptome analysis showed expression of key cell-type-specific genes and the expected alignment with single-cell sequencing and in situ data. Overall, the technique has produced in vitro cell models with characteristics of glia, epithelium, muscle, nerve, and hemocyte. The cells and associated data are available from the Genomic Resource Center.
Topics: Animals; Drosophila; Hemocytes; Neuroglia; Cell Line; Muscles; Drosophila melanogaster
PubMed: 37470241
DOI: 10.7554/eLife.85814 -
ELife Sep 2023Development of the dorsal aorta is a key step in the establishment of the adult blood-forming system, since hematopoietic stem and progenitor cells (HSPCs) arise from...
Development of the dorsal aorta is a key step in the establishment of the adult blood-forming system, since hematopoietic stem and progenitor cells (HSPCs) arise from ventral aortic endothelium in all vertebrate animals studied. Work in zebrafish has demonstrated that arterial and venous endothelial precursors arise from distinct subsets of lateral plate mesoderm. Here, we profile the transcriptome of the earliest detectable endothelial cells (ECs) during zebrafish embryogenesis to demonstrate that tissue-specific EC programs initiate much earlier than previously appreciated, by the end of gastrulation. Classic studies in the chick embryo showed that paraxial mesoderm generates a subset of somite-derived endothelial cells (SDECs) that incorporate into the dorsal aorta to replace HSPCs as they exit the aorta and enter circulation. We describe a conserved program in the zebrafish, where a rare population of endothelial precursors delaminates from the dermomyotome to incorporate exclusively into the developing dorsal aorta. Although SDECs lack hematopoietic potential, they act as a local niche to support the emergence of HSPCs from neighboring hemogenic endothelium. Thus, at least three subsets of ECs contribute to the developing dorsal aorta: vascular ECs, hemogenic ECs, and SDECs. Taken together, our findings indicate that the distinct spatial origins of endothelial precursors dictate different cellular potentials within the developing dorsal aorta.
Topics: Chick Embryo; Animals; Zebrafish; Arteries; Hematopoietic Stem Cells; Hemangioblasts; Aorta
PubMed: 37695317
DOI: 10.7554/eLife.58300 -
Biomedicine & Pharmacotherapy =... Aug 2023Cancer remains a formidable global health challenge, and as such, investigators are constantly exploring underlying mechanisms that drive its progression. One area of... (Review)
Review
Cancer remains a formidable global health challenge, and as such, investigators are constantly exploring underlying mechanisms that drive its progression. One area of interest is the role of lysosomal enzymes, such as cathepsins, in regulating cancer growth and development in the tumour microenvironment (TME). Pericytes, a key component of vasculature, play a key role in regulating blood vessel formation in the TME, have been shown to be influenced by cathepsins and their activity. Although cathepsins such as cathepsins D and L have been shown to induce angiogenesis, currently no direct link is known between pericytes and cathepsins interaction. This review aims to shed light on the potential interplay between pericytes and cathepsins in the TME, highlighting the possible implications for cancer therapy and future research directions.
Topics: Humans; Pericytes; Cathepsins; Tumor Microenvironment; Neoplasms
PubMed: 37236029
DOI: 10.1016/j.biopha.2023.114932 -
Genes Jan 2024Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining... (Review)
Review
Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining vascular integrity, participating in angiogenesis, and regulating blood flow, PCs also serve as a reservoir for multi-potent stem/progenitor cells in white, brown, beige, and bone marrow adipose tissues. Due to the complex nature of this cell population, the identification and characterization of PCs has been challenging. A comprehensive understanding of the heterogeneity of PCs may enhance their potential as therapeutic targets for metabolic syndromes or bone-related diseases. This mini-review summarizes multiple PC markers commonly employed in lineage-tracing studies, with an emphasis on their contribution to adipogenesis and functions in different adipose depots under diverse metabolic conditions.
Topics: Adipogenesis; Pericytes; Adipose Tissue; Stem Cells; Capillaries
PubMed: 38275607
DOI: 10.3390/genes15010126 -
The Journal of Clinical Investigation Dec 2023Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells,...
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In end-stage LAM lung explants, we identified EC dysfunction characterized by increased EC proliferation and migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we used an mTORC1 gain-of-function mouse model with a Tsc2 KO (Tsc2KO) specific to lung mesenchyme (Tbx4LME-Cre Tsc2fl/fl), similar to the mesenchyme-specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from mice exhibited marked transcriptomic changes despite an absence of morphological changes to the distal lung microvasculature. In contrast, 1-year-old Tbx4LME-Cre Tsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single-cell RNA-Seq of 1-year-old mouse lung cells identified paracrine ligands originating from Tsc2KO mesenchyme, which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand-EC receptor crosstalk highlights the importance of an altered mesenchymal cell/EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in patients with LAM and in Tbx4LME-Cre Tsc2fl/fl mice did not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrated dysfunctional EC responses that contributed to pulmonary vascular remodeling.
Topics: Animals; Humans; Infant; Mice; Endothelial Cells; Lung; Lymphangioleiomyomatosis; Mechanistic Target of Rapamycin Complex 1; Mesoderm; Tuberous Sclerosis; Tumor Suppressor Proteins; Vascular Remodeling; T-Box Domain Proteins; Tuberous Sclerosis Complex 2 Protein; In Vitro Techniques
PubMed: 38127441
DOI: 10.1172/JCI172116 -
Cell Death & Disease Oct 2023Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo...
Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo implantation, and dysfunction causes pregnancy failure. Protein glycosylation plays crucial roles in reproduction. However, it remains unclear whether the glycosylation of trophoblasts is involved in trophoblast migration and invasion processes during embryo implantation failure. By Lectin array, we discovered the decreased α1,3-fucosylation, especially difucosylated Lewis Y (LeY) glycan, in the villus tissues of miscarriage patients when compared with normal pregnancy women. Downregulating LeY biosynthesis by silencing the key enzyme fucosyltransferase IV (FUT4) inhibited migration and invasion ability of trophoblast cells. Using proteomics and translatomics, the specific LeY scaffolding glycoprotein of mesoderm-specific transcript (MEST) with glycosylation site at Asn163 was identified, and its expression enhanced migration and invasion ability of trophoblast cells. The results also provided novel evidence showing that decreased LeY modification on MEST hampered the binding of MEST with translation factor eIF4E2, and inhibited implantation-related gene translation initiation, which caused pregnancy failure. The α1,3-fucosylation of MEST by FUT4 may serve as a new biomarker for evaluating the functional state of pregnancy, and a target for infertility treatment.
Topics: Pregnancy; Humans; Female; Glycosylation; Trophoblasts; Embryo Implantation; Epithelial Cells; Biomarkers; Fucosyltransferases
PubMed: 37798282
DOI: 10.1038/s41419-023-06166-4 -
Seminars in Cancer Biology Nov 2023Epithelial-to-mesenchymal transition or transformation (EMT) is a cell shape-changing process that is utilized repeatedly throughout embryogenesis and is critical to the... (Review)
Review
Epithelial-to-mesenchymal transition or transformation (EMT) is a cell shape-changing process that is utilized repeatedly throughout embryogenesis and is critical to the attainment of a precise body plan. In the adult, EMT is observed under both normal and pathological conditions, such as during normal wounding healing, during development of certain fibrotic states and vascular anomalies, as well as in some cancers when malignant cells progress to become more aggressive, invasive, and metastatic. Epithelia derived from any of the three embryonic germ layers can undergo EMT, including those derived from mesoderm, such as endothelial cells (sometimes termed Endo-MT) and those derived from endoderm such as fetal liver stroma. At the cellular level, EMT is defined as the transformation of epithelial cells towards a mesenchymal phenotype and is marked by attenuation of expression of epithelial markers and de novo expression of mesenchymal markers. This process is induced by extracellular factors and can be reversible, resulting in mesenchymal-to-epithelial transformation (MET). It is now clear that a cell can simultaneously express properties of both epithelia and mesenchyme, and that such transitional cell-types drive tumor cell heterogeneity, an important aspect of cancer progression, development of a stem-like cell state, and drug resistance. Here we review some of the earliest studies demonstrating the existence of EMT during embryogenesis and discuss the discovery of the extracellular factors and intracellular signaling pathways that contribute to this process, with components of the TGFβ signaling superfamily playing a prominent role. We mention early controversies surrounding in vivo EMT during embryonic development and in adult diseased states, and the maturation of the field to a stage wherein targeting EMT to control disease states is an aspirational goal.
Topics: Pregnancy; Female; Adult; Humans; Epithelial-Mesenchymal Transition; Endothelial Cells; Epithelial Cells; Neoplasms; Embryonic Development
PubMed: 37852342
DOI: 10.1016/j.semcancer.2023.10.003 -
Stem Cell Research & Therapy Dec 2023With the continuous improvement of human technology, the medical field has gradually moved from molecular therapy to cellular therapy. As a safe and effective... (Review)
Review
With the continuous improvement of human technology, the medical field has gradually moved from molecular therapy to cellular therapy. As a safe and effective therapeutic tool, cell therapy has successfully created a research boom in the modern medical field. Mesenchymal stem cells (MSCs) are derived from early mesoderm and have high self-renewal and multidirectional differentiation ability, and have become one of the important cores of cell therapy research by virtue of their immunomodulatory and tissue repair capabilities. In recent years, the application of MSCs in various diseases has received widespread attention, but there are still various problems in the treatment of MSCs, among which the heterogeneity of MSCs may be one of the causes of the problem. In this paper, we review the correlation of MSCs heterogeneity to provide a basis for further reduction of MSCs heterogeneity and standardization of MSCs and hope to provide a reference for cell therapy.
Topics: Humans; Cell- and Tissue-Based Therapy; Mesenchymal Stem Cells; Cell Differentiation; Mesenchymal Stem Cell Transplantation
PubMed: 38124129
DOI: 10.1186/s13287-023-03587-y -
Biomedicine & Pharmacotherapy =... Dec 2023Pericyte dysfunction and loss contribute substantially to the destabilization and rupture of atherosclerotic plaques. Protocatechuic aldehyde (PCAD), a natural...
Pericyte dysfunction and loss contribute substantially to the destabilization and rupture of atherosclerotic plaques. Protocatechuic aldehyde (PCAD), a natural polyphenol, exerts anti-atherosclerotic effects. However, the effects and mechanisms of this polyphenol on pericyte recruitment, coverage, and pericyte function remain unknown. We here treated apolipoprotein E-deficient mice having high-fat diet-induced atherosclerosis with PCAD. PCAD achieved therapeutic effects similar to rosuvastatin in lowering lipid levels and thus preventing atherosclerosis progression. With PCAD administration, plaque phenotype exhibited higher stability with markedly reduced lesion vulnerability, which is characterized by reduced lipid content and macrophage accumulation, and a consequent increase in collagen deposition. PCAD therapy increased pericyte coverage in the plaques, reduced VEGF-A production, and inhibited intraplaque neovascularization. PCAD promoted pericyte proliferation, adhesion, and migration to mitigate ox-LDL-induced pericyte dysfunction, which thus maintained the capillary network structure and stability. Furthermore, TGFBR1 silencing partially reversed the protective effect exerted by PCAD on human microvascular pericytes. PCAD increased pericyte coverage and impeded ox-LDL-induced damages through TGF-β1/TGFBR1/Smad2/3 signaling. All these novel findings indicated that PCAD increases pericyte coverage and alleviates pericyte damage to improve the stability of atherosclerotic plaques, which is accomplished by regulating TGF-β1/TGFBR1/Smad2/3 signaling in pericytes.
Topics: Animals; Mice; Humans; Plaque, Atherosclerotic; Pericytes; Transforming Growth Factor beta1; Receptor, Transforming Growth Factor-beta Type I; Atherosclerosis; Lipids; Polyphenols
PubMed: 37871558
DOI: 10.1016/j.biopha.2023.115742 -
JCI Insight Jul 2023Pericytes are multipotent mesenchymal precursor cells that demonstrate tissue-specific properties. In this study, by comparing human adipose tissue- and...
Pericytes are multipotent mesenchymal precursor cells that demonstrate tissue-specific properties. In this study, by comparing human adipose tissue- and periosteum-derived pericyte microarrays, we identified T cell lymphoma invasion and metastasis 1 (TIAM1) as a key regulator of cell morphology and differentiation decisions. TIAM1 represented a tissue-specific determinant between predispositions for adipocytic versus osteoblastic differentiation in human adipose tissue-derived pericytes. TIAM1 overexpression promoted an adipogenic phenotype, whereas its downregulation amplified osteogenic differentiation. These results were replicated in vivo, in which TIAM1 misexpression altered bone or adipose tissue generation in an intramuscular xenograft animal model. Changes in pericyte differentiation potential induced by TIAM1 misexpression correlated with actin organization and altered cytoskeletal morphology. Small molecule inhibitors of either small GTPase Rac1 or RhoA/ROCK signaling reversed TIAM1-induced morphology and differentiation in pericytes. In summary, our results demonstrate that TIAM1 regulates the cellular morphology and differentiation potential of human pericytes, representing a molecular switch between osteogenic and adipogenic cell fates.
Topics: Animals; Humans; Actins; Pericytes; Guanine Nucleotide Exchange Factors; Osteogenesis; Cell Differentiation; Adipose Tissue; T-Lymphoma Invasion and Metastasis-inducing Protein 1
PubMed: 37219951
DOI: 10.1172/jci.insight.159141