Parallels between Tooth Development and Repair: Conserved Molecular Mechanisms following Carious and Dental Injury

2004 ◽  
Vol 83 (12) ◽  
pp. 896-902 ◽  
Author(s):  
T.A. Mitsiadis ◽  
C. Rahiotis
Keyword(s):  
Molecular Mechanisms ◽  
Tooth Development ◽  
Cell Movement ◽  
Cell Types ◽  
Matrix Synthesis ◽  
Dental Injury ◽  
Complex Process ◽  
Reparative Dentin ◽  
Pulp Cells ◽  
Collaborative Efforts

The reparative mechanisms that operate following carious and traumatic dental injury are critical for pulp survival and involve a series of highly conserved processes. It appears that these processes share genetic programs—linked to cytoskeletal organization, cell movement, and differentiation—that occur throughout embryogenesis. Reactionary dentin is secreted by surviving odontoblasts in response to moderate stimuli, leading to an increase in metabolic activity. In severe injury, necrotic odontoblasts are replaced by other pulp cells, which are able to differentiate into odontoblast-like cells and produce a reparative dentin. This complex process requires the collaborative efforts of cells of different lineage. The behavior of each of the contributing cell types during the phases of proliferation, migration, and matrix synthesis as well as details of how growth factors control wound cell activities are beginning to emerge. In this review, we discuss what is known about the molecular mechanisms involved in dental repair.

Wound healing and local neuroendocrine regulation in the injured liver

2008 ◽  
Vol 10 ◽  
Author(s):  
Mohammad R. Ebrahimkhani ◽  
Ahmed M. Elsharkawy ◽  
Derek A. Mann
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Neuroendocrine System ◽  
Therapeutic Interventions ◽  
Antifibrotic Therapy ◽  
Complex Process ◽  
Wound Healing Response ◽  
Fibrotic Scar ◽  
Different Cell Types

The hepatic wound-healing response is a complex process involving many different cell types and factors. It leads to the formation of excessive matrix and a fibrotic scar, which ultimately disrupts proper functioning of the liver and establishes cirrhosis. Activated hepatic myofibroblasts, which are derived from cells such as hepatic stellate cells (HSCs), play a key role in this process. Upon chronic liver injury, there is an upregulation in the local neuroendocrine system and it has recently been demonstrated that activated HSCs express specific receptors and respond to different components of this system. Neuroendocrine factors and their receptors participate in a complex network that modulates liver inflammation and wound healing, and controls the development and progression of liver fibrosis. The first part of this review provides an overview of the molecular mechanisms governing hepatic wound healing. In the second section, we explore important components of the hepatic neuroendocrine system and their recently highlighted roles in HSC biology and hepatic fibrogenesis. We discuss the therapeutic interventions that are being developed for use in antifibrotic therapy.

scholarly journals Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 404
Author(s):  
Prabhatchandra Dube ◽  
Armelle DeRiso ◽  
Mitra Patel ◽  
Dhanushya Battepati ◽  
Bella Khatib-Shahidi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Complex Process ◽  
Cardiovascular Morbidity And Mortality ◽  
Depth Analysis ◽  
Multiple Cell ◽  
Different Cell Types

Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease.

scholarly journals The Role of Dendritic Cells during Physiological and Pathological Dentinogenesis

2021 ◽  
Vol 10 (15) ◽  
pp. 3348
Author(s):  
Angela Quispe-Salcedo ◽  
Hayato Ohshima
Keyword(s):  
Dendritic Cells ◽  
Cell Types ◽  
Tooth Injuries ◽  
Tertiary Dentin ◽  
Distinct Cell ◽  
Reparative Dentin ◽  
Pulp Cells ◽  
Antigen Presenting

The dental pulp is a soft connective tissue of ectomesenchymal origin that harbors distinct cell populations, capable of interacting with each other to maintain the vitality of the tooth. After tooth injuries, a sequence of complex biological events takes place in the pulpal tissue to restore its homeostasis. The pulpal response begins with establishing an inflammatory reaction that leads to the formation of a matrix of reactionary or reparative dentin, according to the nature of the exogenous stimuli. Using several in vivo designs, antigen-presenting cells, including macrophages and dendritic cells (DCs), are identified in the pulpal tissue before tertiary dentin deposition under the afflicted area. However, the precise nature of this phenomenon and its relationship to inherent pulp cells are not yet clarified. This literature review aims to discuss the role of pulpal DCs and their relationship to progenitor/stem cells, odontoblasts or odontoblast-like cells, and other immunocompetent cells during physiological and pathological dentinogenesis. The concept of “dentin-pulp immunology” is proposed for understanding the crosstalk among these cell types after tooth injuries, and the possibility of immune-based therapies is introduced to accelerate pulpal healing after exogenous stimuli.

scholarly journals Negative durotaxis: cell movement toward softer environments

2020 ◽  
Author(s):  
Aleksi Isomursu ◽  
Keun-Young Park ◽  
Jay Hou ◽  
Bo Cheng ◽  
Ghaidan Shamsan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Movement ◽  
Cell Types ◽  
Force Transmission ◽  
Glioblastoma Cells ◽  
Genetic Manipulations ◽  
Cellular Processes ◽  
Actomyosin Contractility ◽  
Migratory Cells ◽  
Optimal Stiffness

AbstractDurotaxis – the ability of cells to sense and migrate along stiffness gradients – is important for embryonic development and has been implicated in pathologies including fibrosis and cancer. Although cellular processes can sometimes turn toward softer environments, durotaxis at the level of cells has thus far been observed exclusively as migration from soft to stiff regions. The molecular basis of durotaxis, especially the factors that contribute to different durotactic behaviors in various cell types, are still inadequately understood. With the recent discovery of ‘optimal stiffness’, where cells generate maximal traction forces on substrates in an intermediate stiffness range, we hypothesized that some migratory cells may be capable of moving away from stiff environments and toward matrix on which they can generate more traction. Combining hydrogel-based stiffness gradients, live-cell imaging, genetic manipulations, and computational modeling, we found that cells move preferentially toward their stiffness optimum for maximal force transmission. Importantly, we directly observed biased migration toward softer environments, i.e. ‘negative durotaxis’, in human glioblastoma cells. This directional migration did not coincide with changes in FAK, ERK or YAP signaling, or with altered actomyosin contractility. Instead, integrin-mediated adhesion and motor-clutch dynamics alone are sufficient to generate asymmetric traction to drive both positive and negative durotaxis. We verified this mechanistically by applying a motor-clutch-based model to explain negative durotaxis in the glioblastoma cells and in neurites, and experimentally by switching breast cancer cells from positive to negative durotaxis via talin downregulation. Our results identify the likely molecular mechanisms of durotaxis, with a cell’s contractile and adhesive machinery dictating its capacity to exert traction on mechanically distinct substrates, directing cell migration.

scholarly journals Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ofir Klein ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Cell Types ◽  
Secretory Cells ◽  
Regulated Exocytosis ◽  
Open Questions ◽  
Conflicting Evidence ◽  
Compound Exocytosis

Anaphylaxis is a notorious type 2 immune response which may result in a systemic response and lead to death. A precondition for the unfolding of the anaphylactic shock is the secretion of inflammatory mediators from mast cells in response to an allergen, mostly through activation of the cells via the IgE-dependent pathway. While mast cells are specialized secretory cells that can secrete through a variety of exocytic modes, the most predominant mode exerted by the mast cell during anaphylaxis is compound exocytosis—a specialized form of regulated exocytosis where secretory granules fuse to one another. Here, we review the modes of regulated exocytosis in the mast cell and focus on compound exocytosis. We review historical landmarks in the research of compound exocytosis in mast cells and the methods available for investigating compound exocytosis. We also review the molecular mechanisms reported to underlie compound exocytosis in mast cells and expand further with reviewing key findings from other cell types. Finally, we discuss the possible reasons for the mast cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence in different mast cell models, and the open questions in the field which remain to be answered.

scholarly journals Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9036
Author(s):  
Sara Saez-Atienzar ◽  
Sara Bandres-Ciga ◽  
Rebekah G. Langston ◽  
Jonggeol J. Kim ◽  
Shing Wan Choi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Data Driven Approach ◽  
Single Nucleus ◽  
Lateral Sclerosis

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

scholarly journals In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kolja Becker ◽  
Holger Klein ◽  
Eric Simon ◽  
Coralie Viollet ◽  
Christian Haslinger ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Expression Profiles ◽  
Cell Types ◽  
Sequencing Data ◽  
Disease Stages ◽  
Post Transcriptional Regulation

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

scholarly journals MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1074
Author(s):  
Giuseppina Divisato ◽  
Silvia Piscitelli ◽  
Mariantonietta Elia ◽  
Emanuela Cascone ◽  
Silvia Parisi
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Cell Types ◽  
Cancer Development ◽  
Special Focus ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Exploring the Intracrine Functions of VEGF-A

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Sophie Wiszniak ◽  
Quenten Schwarz
Keyword(s):  
Cell Growth ◽  
Molecular Mechanisms ◽  
Direct Action ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Vascular Endothelial ◽  
Signalling Molecule ◽  
Endothelial Growth Factor ◽  
Important Signalling Molecule ◽  
Vegf Signalling

Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed “intracrine”, and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics.

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