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Cells Nov 2021The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is... (Review)
Review
The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is composed of the following phases: G1, S, G2, and M phase. Cell cycle progression is mediated by cyclin-dependent kinases (Cdks) and their regulatory cyclin subunits. However, the driving force of cell cycle progression is growth factor-initiated signaling pathways that control the activity of various Cdk-cyclin complexes. While the mechanism underlying the role of growth factor signaling in G1 phase of cell cycle progression has been largely revealed due to early extensive research, little is known regarding the function and mechanism of growth factor signaling in regulating other phases of the cell cycle, including S, G2, and M phase. In this review, we briefly discuss the process of cell cycle progression through various phases, and we focus on the role of signaling pathways activated by growth factors and their receptor (mostly receptor tyrosine kinases) in regulating cell cycle progression through various phases.
Topics: Animals; Cell Cycle; Humans; Intercellular Signaling Peptides and Proteins; Models, Biological; Signal Transduction
PubMed: 34943835
DOI: 10.3390/cells10123327 -
Clinical Oral Investigations Dec 2016The use of platelet concentrates has gained increasing awareness in recent years for regenerative procedures in modern dentistry. The aim of the present study was to... (Comparative Study)
Comparative Study
OBJECTIVES
The use of platelet concentrates has gained increasing awareness in recent years for regenerative procedures in modern dentistry. The aim of the present study was to compare growth factor release over time from platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and a modernized protocol for PRF, advanced-PRF (A-PRF).
MATERIALS AND METHODS
Eighteen blood samples were collected from six donors (3 samples each for PRP, PRF, and A-PRF). Following preparation, samples were incubated in a plate shaker and assessed for growth factor release at 15 min, 60 min, 8 h, 1 day, 3 days, and 10 days. Thereafter, growth factor release of PDGF-AA, PDGF-AB, PDGF-BB, TGFB1, VEGF, EGF, and IGF was quantified using ELISA.
RESULTS
The highest reported growth factor released from platelet concentrates was PDGF-AA followed by PDGF-BB, TGFB1, VEGF, and PDGF-AB. In general, following 15-60 min incubation, PRP released significantly higher growth factors when compared to PRF and A-PRF. At later time points up to 10 days, it was routinely found that A-PRF released the highest total growth factors. Furthermore, A-PRF released significantly higher total protein accumulated over a 10-day period when compared to PRP or PRF.
CONCLUSION
The results from the present study indicate that the various platelet concentrates have quite different release kinetics. The advantage of PRP is the release of significantly higher proteins at earlier time points whereas PRF displayed a continual and steady release of growth factors over a 10-day period. Furthermore, in general, it was observed that the new formulation of PRF (A-PRF) released significantly higher total quantities of growth factors when compared to traditional PRF.
CLINICAL RELEVANCE
Based on these findings, PRP can be recommended for fast delivery of growth factors whereas A-PRF is better-suited for long-term release.
Topics: Adult; Blood Platelets; Enzyme-Linked Immunosorbent Assay; Fibrin; Humans; Intercellular Signaling Peptides and Proteins; Middle Aged; Platelet-Rich Plasma
PubMed: 26809431
DOI: 10.1007/s00784-016-1719-1 -
Cells Aug 2021In this article we review the cellular and molecular mechanisms of gastric ulcer healing. A gastric ulcer (GU) is a deep defect in the gastric wall penetrating through... (Review)
Review
In this article we review the cellular and molecular mechanisms of gastric ulcer healing. A gastric ulcer (GU) is a deep defect in the gastric wall penetrating through the entire mucosa and the muscularis mucosae. GU healing is a regeneration process that encompasses cell dedifferentiation, proliferation, migration, re-epithelialization, formation of granulation tissue, angiogenesis, vasculogenesis, interactions between various cells and the matrix, and tissue remodeling, all resulting in scar formation. All these events are controlled by cytokines and growth factors (e.g., EGF, TGFα, IGF-1, HGF, bFGF, TGFβ, NGF, VEGF, angiopoietins) and transcription factors activated by tissue injury. These growth factors bind to their receptors and trigger cell proliferation, migration, and survival pathways through Ras, MAPK, PI3K/Akt, PLC-γ, and Rho/Rac/actin signaling. The triggers for the activation of these growth factors are tissue injury and hypoxia. EGF, its receptor, IGF-1, HGF, and COX-2 are important for epithelial cell proliferation, migration, re-epithelialization, and gastric gland reconstruction. VEGF, angiopoietins, bFGF, and NGF are crucial for blood vessel regeneration in GU scars. The serum response factor (SRF) is essential for VEGF-induced angiogenesis, re-epithelialization, and blood vessel and muscle restoration. Local therapy with cDNA of human recombinant VEGF165 in combination with angiopoietin1, or with the NGF protein, dramatically accelerates GU healing and improves the quality of mucosal restoration within ulcer scars. The future directions for accelerating and improving healing include local gene and protein therapies with growth factors, their combinations, and the use of stem cells and tissue engineering.
Topics: Animals; Cytokines; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Neovascularization, Physiologic; Nerve Growth Factor; Signal Transduction; Stomach Ulcer; Transcription Factors
PubMed: 34440733
DOI: 10.3390/cells10081964 -
International Journal of Molecular... Oct 2020The complex tissue engineering/regenerative medicine now represents a therapeutic reality applicable to various organic substrates, with the aim of repairing deficient...
The complex tissue engineering/regenerative medicine now represents a therapeutic reality applicable to various organic substrates, with the aim of repairing deficient tissues and restoring normal organ function. Among the possible specialized uses, in the dental field, the treatment of periodontal, pre- and peri-implant bone defects should be mentioned. Nowadays, in oral surgery, there are many surgical methods that can be used, despite that the literature still seems controversial regarding the actual advantages of their use. Surely, this work will bring to light the current clinical-surgical orientations and the different perspectives.
Topics: Guided Tissue Regeneration, Periodontal; Humans; Intercellular Signaling Peptides and Proteins; Oral Surgical Procedures; Regenerative Medicine; Wound Healing
PubMed: 33092073
DOI: 10.3390/ijms21207752 -
Philosophical Transactions of the Royal... Feb 2019Macropinocytosis is an evolutionarily conserved form of endocytosis that mediates non-selective uptake of extracellular fluid and the solutes contained therein. In... (Review)
Review
Macropinocytosis is an evolutionarily conserved form of endocytosis that mediates non-selective uptake of extracellular fluid and the solutes contained therein. In mammalian cells, macropinocytosis is initiated by growth factor-mediated activation of the Ras and PI3-kinase signalling pathways. In malignant cells, oncogenic activation of growth factor signalling sustains macropinocytosis cell autonomously. Recent studies of cancer metabolism, discussed here, have begun to define a role for macropinocytosis as a nutrient uptake route. Macropinocytic cancer cells ingest macromolecules in bulk and break them down in the lysosome to support metabolism and macromolecular synthesis. Thereby, macropinocytosis allows cells to tap into the copious nutrient stores of extracellular macromolecules when canonical nutrients are scarce. These findings demonstrate that macropinocytosis promotes metabolic flexibility and resilience, which enables cancer cells to survive and grow in nutrient-poor environments. Implications for physiological roles of growth factor-stimulated macropinocytosis in cell metabolism and its relationship with other nutrient uptake pathways are considered. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.
Topics: Animals; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Pinocytosis; Signal Transduction
PubMed: 30967008
DOI: 10.1098/rstb.2018.0285 -
Cytokine & Growth Factor Reviews Feb 2017Cytokines and growth factors regulate cell proliferation, differentiation, migration and apoptosis, and play important roles in coordinating growth signal responses... (Review)
Review
Cytokines and growth factors regulate cell proliferation, differentiation, migration and apoptosis, and play important roles in coordinating growth signal responses during development. The expression of cytokine genes and the signals transmitted through cytokine receptors are tightly regulated at several levels, including transcriptional and post-transcriptional levels. A majority of cytokine mRNAs, including growth factor transcripts, contain AU-rich elements (AREs) in their 3' untranslated regions that control gene expression by regulating mRNA degradation and changing translational rates. In addition, numerous proteins involved in transmitting signals downstream of cytokine receptors are regulated at the level of mRNA degradation by GU-rich elements (GREs) found in their 3' untranslated regions. Abnormal stabilization and overexpression of ARE or GRE-containing transcripts had been observed in many malignancies, which is a consequence of the malfunction of RNA-binding proteins. In this review, we briefly summarize the role of AREs and GREs in regulating mRNA turnover to coordinate cytokine and growth factor expression, and we describe how dysregulation of mRNA degradation mechanisms contributes to the development and progression of cancer.
Topics: 3' Untranslated Regions; Animals; Apoptosis; Cytokines; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins; Mice; Neoplasms; Protein Processing, Post-Translational; RNA Stability; Receptors, Cytokine; Signal Transduction
PubMed: 27956133
DOI: 10.1016/j.cytogfr.2016.11.004 -
The Journal of Clinical Investigation Mar 2003Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely...
Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.
Topics: Endothelial Growth Factors; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney; Lymphokines; Neovascularization, Physiologic; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Proteinuria; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors
PubMed: 12618519
DOI: 10.1172/JCI17189 -
Advanced Healthcare Materials Aug 2017Engineering cellular microenvironments involves biochemical factors, the extracellular matrix (ECM) and the interaction with neighbouring cells. This progress report... (Review)
Review
Engineering cellular microenvironments involves biochemical factors, the extracellular matrix (ECM) and the interaction with neighbouring cells. This progress report provides a critical overview of key studies that incorporate growth factor (GF) signalling and mechanotransduction into the design of advanced microenvironments. Materials systems have been developed for surface-bound presentation of GFs, either covalently tethered or sequestered through physico-chemical affinity to the matrix, as an alternative to soluble GFs. Furthermore, some materials contain both GF and integrin binding regions and thereby enable synergistic signalling between the two. Mechanotransduction refers to the ability of the cells to sense physical properties of the ECM and to transduce them into biochemical signals. Various aspects of the physics of the ECM, i.e. stiffness, geometry and ligand spacing, as well as time-dependent properties, such as matrix stiffening, degradability, viscoelasticity, surface mobility as well as spatial patterns and gradients of physical cues are discussed. To conclude, various examples illustrate the potential for cooperative signalling of growth factors and the physical properties of the microenvironment for potential applications in regenerative medicine, cancer research and drug testing.
Topics: Animals; Cell Proliferation; Cellular Microenvironment; Elastic Modulus; Extracellular Matrix; Humans; Intercellular Signaling Peptides and Proteins; Mechanotransduction, Cellular; Stress, Mechanical; Tissue Engineering
PubMed: 28792683
DOI: 10.1002/adhm.201700052 -
Biomaterials Advances Mar 2023Addressing clinical challenges for tendon injuries requires a deeper understanding of the effects that biological and biophysical cues have on tenogenesis. Although...
Addressing clinical challenges for tendon injuries requires a deeper understanding of the effects that biological and biophysical cues have on tenogenesis. Although prior studies have identified tenogenic growth factors (GFs) or elucidated the effects of substrate topography on tenocyte behavior, few have characterized their combined effect in the presence of a tendon-like substrate. In this study, we assessed the effect of biological (GFs) and biophysical (substrate topography) cues on tenogenic proliferation and differentiation under defined, serum-free conditions. Specifically, human bone marrow-derived mesenchymal stem cells (hMSCs) were cultured in a serum-free culture medium containing a GF cocktail comprised of fibroblast growth factor-2 (FGF-2), transforming growth factor-beta 3 (TGF-β3), and insulin-like growth factor-1 (IGF-1), either alone or in combination with tendon-like substrate topography produced by replica casting of tendon tissue sections. Our data demonstrated that the use of serum-free GF cocktail medium alone promoted hMSC proliferation, as shown via DNA staining as well as Ki67 protein levels and gene expression. In particular, gene expression of Ki67 was increased by 8.46-fold in all three donors relative to serum-free medium control. Also, serum-free GF cocktail promoted tenogenic differentiation, on the basis of expression of tendon-associated gene and protein markers, scleraxis (SCX), tenascin C (TNC), and collagen type I (COL1A1) including increased normalized collagen production by 1.4-fold in two donors relative to serum-free medium control. Interestingly, hMSCs cultured on a tendon-like substrate exhibited highly oriented cell morphology and extracellular matrix (ECM) alignment reminiscent of tendon. In particular, when this GF cocktail was combined with tendon-like topography, they showed a synergistically increased expression of tendon-related markers and anisotropic organization of ECM proteins with moderate-to-large effect sizes. Together, in addition to showing the utility of a GF cocktail for expansion and differentiation of tenocyte-like cells, our findings clearly demonstrate the synergistic relationship between GF-mediated and substrate topography-related effects on hMSC tenogenic differentiation. This information provides insights into the design of strategies that combine biological and biophysical cues for ex vivo tenocyte production and tendon tissue engineering.
Topics: Humans; Ki-67 Antigen; Tendons; Cell Differentiation; Mesenchymal Stem Cells; Intercellular Signaling Peptides and Proteins
PubMed: 36736265
DOI: 10.1016/j.bioadv.2023.213316 -
International Journal of Nanomedicine 2020The development of biomaterials, stem cells and bioactive factors has led to cartilage tissue engineering becoming a promising tactic to repair cartilage defects.... (Review)
Review
The development of biomaterials, stem cells and bioactive factors has led to cartilage tissue engineering becoming a promising tactic to repair cartilage defects. Various polymer three-dimensional scaffolds that provide an extracellular matrix (ECM) mimicking environment play an important role in promoting cartilage regeneration. In addition, numerous growth factors have been found in the regenerative process. However, it has been elucidated that the uncontrolled delivery of these factors cannot fully exert regenerative potential and can also elicit undesired side effects. Considering the complexity of the ECM, neither scaffolds nor growth factors can independently obtain successful outcomes in cartilage tissue engineering. Therefore, collectively, an appropriate combination of growth factors and scaffolds have great potential to promote cartilage repair effectively; this approach has become an area of considerable interest in recent investigations. Of late, an increasing trend was observed in cartilage tissue engineering towards this combination to develop a controlled delivery system that provides adequate physical support for neo-cartilage formation and also enables spatiotemporally delivery of growth factors to precisely and fully exert their chondrogenic potential. This review will discuss the role of polymer scaffolds and various growth factors involved in cartilage tissue engineering. Several growth factor delivery strategies based on the polymer scaffolds will also be discussed, with examples from recent studies highlighting the importance of spatiotemporal strategies for the controlled delivery of single or multiple growth factors in cartilage tissue engineering applications.
Topics: Animals; Biocompatible Materials; Cartilage; Chondrogenesis; Extracellular Matrix; Humans; Intercellular Signaling Peptides and Proteins; Polymers; Stem Cells; Tissue Engineering; Tissue Scaffolds
PubMed: 32884266
DOI: 10.2147/IJN.S249829