Calcium Signaling is a Key Regulator of Mesenchymal Stem Cell Response to Hydrostatic Pressure

2013 ◽  
Author(s):  
A. J. Steward ◽  
D. J. Kelly ◽  
D. R. Wagner
Keyword(s):  
Hydrostatic Pressure ◽  
Calcium Signaling ◽  
Cellular Response ◽  
Cellular Proliferation ◽  
Cartilaginous Tissues ◽  
Compressive Loads ◽  
Fluid Pressurization ◽  
Matrix Accumulation

Fluid pressurization is the dominant load-bearing mechanism of the in vivo joint environment, supporting up to 90% of compressive loads in cartilage[1]. In accordance with its prominence in cartilaginous tissues, hydrostatic pressure (HP) significantly enhances the chondrogenic differentiation of mesenchymal stem cells (MSCs) [2,3]. However, surprisingly little is known about the mechanisms by which cells sense HP and translate it into a biochemical signal. This is partly due to the fact that HP generates a state of stress with little deformation, as hydrated tissues and cells are nearly incompressible. Because of this, it has been assumed that HP mechanotransduction differs from that of other mechanical loads which deform the cells [4]. Recently, we demonstrated that integrin binding to the pericellular matrix (PCM) regulates the cytoskeletal organization of MSCs, and this in turn determines their response to HP [5]. Another proposed mechanism of HP mechanotransduction is fluctuations in intracellular ion concentrations, which are altered by the application of HP [6–8]. In particular, calcium signaling has been implicated as a key regulator of cellular response in other mechanical loading modalities, yet no studies have examined the role of calcium in the response of MSCs to HP. Therefore the objective of this study was to examine the cellular proliferation and chondrogenic matrix accumulation of MSCs in response to HP in the presence of pharmacological inhibitors of calcium ion mobility in order to elucidate the role of calcium signaling in the mechanotransduction of HP.

scholarly journals Oxidized LDLs as Signaling Molecules

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1184
Author(s):  
Jean-Marc Zingg ◽  
Adelina Vlad ◽  
Roberta Ricciarelli
Keyword(s):  
Free Radicals ◽  
Cellular Response ◽  
Vascular System ◽  
Signaling Molecules ◽  
Scavenger Receptors ◽  
Physiological Relevance ◽  
Reactive Radicals ◽  
Accumulation Of Lipids

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

scholarly journals The Role of Biomimetic Hypoxia on Cancer Cell Behaviour in 3D Models: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1334
Author(s):  
Ye Liu ◽  
Zahra Mohri ◽  
Wissal Alsheikh ◽  
Umber Cheema
Keyword(s):  
Systematic Review ◽  
Cellular Response ◽  
3D Culture ◽  
3D Models ◽  
In Vitro Models ◽  
Research Findings ◽  
Tissue Models

The development of biomimetic, human tissue models is recognized as being an important step for transitioning in vitro research findings to the native in vivo response. Oftentimes, 2D models lack the necessary complexity to truly recapitulate cellular responses. The introduction of physiological features into 3D models informs us of how each component feature alters specific cellular response. We conducted a systematic review of research papers where the focus was the introduction of key biomimetic features into in vitro models of cancer, including 3D culture and hypoxia. We analysed outcomes from these and compiled our findings into distinct groupings to ascertain which biomimetic parameters correlated with specific responses. We found a number of biomimetic features which primed cancer cells to respond in a manner which matched in vivo response.

scholarly journals The roles of distinct Ca2+ signaling mediated by Piezo and inositol triphosphate receptor (IP3R) in the remodeling of E-cadherin during cell dissemination

2021 ◽  
Author(s):  
Alejandra J.H. Cabrera ◽  
Barry M Gumbiner ◽  
Young V Kwon
Keyword(s):  
Calcium Signaling ◽  
Intracellular Calcium ◽  
Cell Invasion ◽  
Adherens Junctions ◽  
Transformed Cells ◽  
Inositol Triphosphate ◽  
Intracellular Calcium Signaling ◽  
Cell Dissemination

Given the role of E-cadherin (E-cad) in holding epithelial cells together, the inverse relationship between E-cad levels and cell invasion has been perceived as a principle underlying the invasiveness of tumor cells. In contrast, our study employing the Drosophila model of cell dissemination demonstrates that E-cad is necessary for the invasiveness of RasV12-transformed cells in vivo. Drosophila E-cad/β-catenin disassembles at adherens junctions and assembles at invasive protrusions—the actin- and cortactin-rich invadopodia-like protrusions associated with breach of the extracellular matrix (ECM)—during cell dissemination. Loss of E-cad attenuates dissemination of RasV12-transformed cells by impairing their ability to compromise the ECM. Strikingly, the remodeling of E-cad/β-catenin subcellular distribution is controlled by two discrete intracellular calcium signaling pathways: Ca2+ release from endoplasmic reticulum via the inositol triphosphate receptor (IP3R) disassembles E-cad at adherens junctions while Ca2+ entry via the mechanosensitive channel Piezo assembles E-cad at invasive protrusions. Thus, our study provides molecular insights into the unconventional role of E-cad in cell invasion during cell dissemination in vivo and describes the discrete roles of intracellular calcium signaling in the remodeling of E-cad/β-catenin subcellular localization.

scholarly journals HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fengjie Jiang ◽  
Xiaozhu Tang ◽  
Chao Tang ◽  
Zhen Hua ◽  
Mengying Ke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Aberrant Expression ◽  
The Stability ◽  
Induced Apoptosis ◽  
Proliferation In Vitro

AbstractN6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic RNAs while accumulating studies suggest that m6A aberrant expression plays an important role in cancer. HNRNPA2B1 is a m6A reader which binds to nascent RNA and thus affects a perplexing array of RNA metabolism exquisitely. Despite unveiled facets that HNRNPA2B1 is deregulated in several tumors and facilitates tumor growth, a clear role of HNRNPA2B1 in multiple myeloma (MM) remains elusive. Herein, we analyzed the function and the regulatory mechanism of HNRNPA2B1 in MM. We found that HNRNPA2B1 was elevated in MM patients and negatively correlated with favorable prognosis. The depletion of HNRNPA2B1 in MM cells inhibited cell proliferation and induced apoptosis. On the contrary, the overexpression of HNRNPA2B1 promoted cell proliferation in vitro and in vivo. Mechanistic studies revealed that HNRNPA2B1 recognized the m6A sites of ILF3 and enhanced the stability of ILF3 mRNA transcripts, while AKT3 downregulation by siRNA abrogated the cellular proliferation induced by HNRNPA2B1 overexpression. Additionally, the expression of HNRNPA2B1, ILF3 and AKT3 was positively associated with each other in MM tissues tested by immunohistochemistry. In summary, our study highlights that HNRNPA2B1 potentially acts as a therapeutic target of MM through regulating AKT3 expression mediated by ILF3-dependent pattern.

scholarly journals Modulation of mTORC1 Signaling Pathway by HIV-1

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1090 ◽  
Author(s):  
Burkitkan Akbay ◽  
Anna Shmakova ◽  
Yegor Vassetzky ◽  
Svetlana Dokudovskaya
Keyword(s):  
Cellular Response ◽  
Cellular Proliferation ◽  
Mammalian Target Of Rapamycin ◽  
Host Cells ◽  
Promising Strategy ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Recent Trends ◽  
Hiv 1

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular proliferation and survival which controls cellular response to different stresses, including viral infection. HIV-1 interferes with the mTORC1 pathway at every stage of infection. At the same time, the host cells rely on the mTORC1 pathway and autophagy to fight against virus replication and transmission. In this review, we will provide the most up-to-date picture of the role of the mTORC1 pathway in the HIV-1 life cycle, latency and HIV-related diseases. We will also provide an overview of recent trends in the targeting of the mTORC1 pathway as a promising strategy for HIV-1 eradication.

Development and Validation of a System for the Growth of Cells and Tissues Under Intermittent Hydrostatic Pressure

2008 ◽  
Vol 130 (6) ◽  
Author(s):  
Troy J. Eggum ◽  
Christopher J. Hunter
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hydrostatic Pressure ◽  
Intervertebral Disk ◽  
3T3 Fibroblasts ◽  
Or Methodology ◽  
Environmental Stimulation ◽  
Nih 3T3

Various cell populations have been shown to respond to hydrostatic pressure; however, many of the culture systems suffer from shortcomings in design or methodology. Of particular interest to us is the potential role of pressure and other environmental factors in modulating stem cell behavior in intervertebral disk repair. A system was developed for the growth of cells and tissues under intermittent hydrostatic pressure. The system was validated with NIH 3T3 fibroblasts for sterilizability and cytotoxicity. Further experiments were conducted with canine mesenchymal stem cells under various levels of pressure, oxygen, glucose, and conditioned medium. The culture system showed no cytotoxicity and was able to demonstrate that the proliferation and metabolism of mesenchymal stem cells are sensitive to medium glucose and oxygen concentration and hydrostatic pressure. The cells exposed to hydrostatic pressure differed in their morphology from nonexposed cells. The system is capable of supporting long-term cell culture and examining the role of mechanical and environmental stimulation in vivo.

scholarly journals Involvement of I-BAR protein IRSp53 in tumor cell growth via extracellular microvesicle secretion

2020 ◽  
Author(s):  
Hooi Ting Hu ◽  
Naoto Sasakura ◽  
Daisuke Matsubara ◽  
Naoko Furusawa ◽  
Masahiro Mukai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Culture Medium ◽  
Cellular Proliferation ◽  
Squamous Carcinoma ◽  
Mitogen Activated Protein Kinase ◽  
Mice Model ◽  
Bar Domain ◽  
Mitogen Activated Protein

AbstractCellular protrusions mediated by the membrane-deforming I-BAR domain protein IRSp53 are involved in cell migration, including metastasis. However, the role of IRSp53 in cell proliferation remains unclear. Here, we examined the role of IRSp53 in cell proliferation and found that it acts through secretion. Coculture of gingiva squamous carcinoma Ca9-22 cells and their IRSp53-knockout cells restored proliferation to parental Ca9-22 cell levels, suggesting possible secretion dependent on IRSp53. Notably, the amounts of microvesicle fraction proteins that were secreted into the culture medium were reduced in the IRSp53-knockout cells. The IRSp53-knockout cells exhibited decreased phosphorylation of mitogen-activated protein kinase, suggesting the decrease in the proliferation signals. The phosphorylation was restored by the addition of the microvesicles. In mice xenograft Ca9-22 cells, IRSp53-containing particles were secreted around the xenograft, indicating that IRSp53-dependent secretion occurs in vivo. In a tumor mice model, IRSp53 deficiency elongated lifespan. In some human cancers, the higher levels of IRSp53 mRNA expression was found to be correlated with shorter survival years. Therefore, IRSp53 is involved in tumor progression and secretion for cellular proliferation.

scholarly journals Activation of the Hypoxia-Inducible Factor Pathway Expands Early Thymic Progenitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2896-2896
Author(s):  
Anita Hollenbeck ◽  
Stefanie Weber ◽  
Kathrin Händschke ◽  
Mandy Necke ◽  
Bertram Opalka ◽  
...  
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Cell Receptor ◽  
Normal Numbers ◽  
Cellular Compartment ◽  
Vhl Gene ◽  
Von Hippel Lindau

Abstract Early thymic progenitors enter the thymus and are exposed to regional hypoxia while they develop in a step-wise manner to mature functional T-cells. Therefore, hypoxia might represent an important component of the highly specialized thymic microenvironment. On the molecular level the hypoxia-inducible factor pathway controls the cellular response to hypoxia. In this pathway, the von-Hippel-Lindau protein (pVHL) continuously mediates the destruction of the transcription factor hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions. Under hypoxia HIF-1α degradation is inhibited leading to the activation of HIF-1α target genes. Others used lck-Cre transgene-mediated conditional in vivo deletion of the Vhl gene to study the role of the oxygen-sensing pathway in developing thymocytes and found normal numbers of early double-negative (DN; CD4-CD8-) thymocytes (Biju et al., Mol Cell Biol, 2004). However, lck-Cre deletion initiates at the DN3 (CD25+CD44-) stage leaving the Vhl locus of very early DN1 (CD25-CD44+), DN2 (CD25+CD44+) and DN3 thymocytes unaltered. Therefore, we here used the ubiquitous hematopoietic deleter strain vav-Cre to investigate the role of pVHL in very early thymocytes (vav-Cre;VhlloxP;loxP mice). Using a PCR-based strategy we confirmed complete deletion of the Vhl gene in this model. We observed unaltered DN1 and DN2 progenitor numbers, however in contrast to the published lck-cre-mediated system we consistently observed an up to twofold expansion of the DN3 cellular compartment. As the hypoxia-inducible factor pathway was shown to modulate NOTCH1 signaling we studied Notch1 expression on Vhl-deficient thymocytes. Strikingly, Notch1 expression was significantly increased on expanded Vhl null DN3 thymocytes. At the DN3 developmental stage selection of cells with an accurately re-arranged T-cell receptor β-locus occurs. Thus, we analyzed pre- and post-β-selection DN3 cells by CD28 staining. Interestingly, we found both pre- and post-β-selection DN3 subpopulations expanded. In order to investigate whether the progenitor expansion is mediated by the lack of HIF-1α inhibition in the Vhl-deficient context we studied DN3 thymocytes in a conditional hematopoietic HIF-1α gain-of-function model (vav-Cre;HIF1dPA). Overexpression of HIF-1α, which is insensitive to pVHL-mediated degradation in vav-Cre;HIF1dPAmice, also resulted in expanded DN3 thymocytes. In summary, we describe novel conditional models to genetically alter the hypoxia-inducible factor pathway within very early thymic progenitors. Genetic Vhl loss led to an expansion of DN3 thymocytes. This DN3 expansion is most likely due to the absence of HIF-1α-inhibition, because HIF-1α overexpression phenocopied the Vhl-deficient DN3 thymocyte expansion. Disclosures Dührsen: Celgene: Honoraria, Research Funding.

scholarly journals Comparison of Cytomorphometry and Early Cell Response of Human Gingival Fibroblast (HGFs) between Zirconium and New Zirconia-Reinforced Lithium Silicate Ceramics (ZLS)

2018 ◽  
Vol 19 (9) ◽  
pp. 2718 ◽  
Author(s):  
María Rizo-Gorrita ◽  
Irene Luna-Oliva ◽  
María-Ángeles Serrera-Figallo ◽  
José-Luis Gutiérrez-Pérez ◽  
Daniel Torres-Lagares
Keyword(s):  
Cellular Response ◽  
Surface Characterization ◽  
Cellular Proliferation ◽  
Lithium Silicate ◽  
Human Gingival Fibroblast ◽  
Gingival Fibroblast ◽  
Gingival Fibroblasts ◽  
Optical Profilometry

New zirconia-reinforced lithium silicate ceramics (ZLS) could be a viable alternative to zirconium (Y-TZP) in the manufacture of implantological abutments—especially in aesthetic cases—due to its good mechanical, optical, and biocompatibility properties. Although there are several studies on the ZLS mechanical properties, there are no studies regarding proliferation, spreading, or cytomorphometry. We designed the present study which compares the surface, cellular proliferation, and cellular morphology between Y-TZP (Vita YZ® T [Vita Zahnfabrik (Postfach, Germany)]) and ZLS (Celtra® Duo [Degudent (Hanau-Wolfgang, Germany)]). The surface characterization was performed with energy dispersive spectroscopy (EDS), scanning electron microscopy (SEM), and optical profilometry. Human gingival fibroblasts (HGFs) were subsequently cultured on both materials and early cellular response and cell morphology were compared through nuclear and cytoskeletal measurement parameters using confocal microscopy. The results showed greater proliferation and spreading on the surface of Y-TZP. This could indicate that Y-TZP continues to be a gold standard in terms of transgingival implant material: Nevertheless, more in vitro and in vivo research is necessary to confirm the results obtained in this study.

scholarly journals Osteoblast Autonomous Pi Regulation via Pit1 Plays a Role in Bone Mineralization

2007 ◽  
Vol 27 (12) ◽  
pp. 4465-4474 ◽  
Author(s):  
Yuji Yoshiko ◽  
G. Antonio Candeliere ◽  
Norihiko Maeda ◽  
Jane E. Aubin
Keyword(s):  
Cellular Proliferation ◽  
Bone Mineralization ◽  
Regulatory System ◽  
Early Response ◽  
In Vitro Models ◽  
Skeletal Tissue ◽  
Rate Limiting Step

ABSTRACT The complex pathogenesis of mineralization defects seen in inherited and/or acquired hypophosphatemic disorders suggests that local inorganic phosphate (Pi) regulation by osteoblasts may be a rate-limiting step in physiological bone mineralization. To test whether an osteoblast autonomous phosphate regulatory system regulates mineralization, we manipulated well-established in vivo and in vitro models to study mineralization stages separately from cellular proliferation/differentiation stages of osteogenesis. Foscarnet, an inhibitor of NaPi transport, blocked mineralization of osteoid formation in osteoblast cultures and local mineralization after injection over the calvariae of newborn rats. Mineralization was also down- and upregulated, respectively, with under- and overexpression of the type III NaPi transporter Pit1 in osteoblast cultures. Among molecules expressed in osteoblasts and known to be related to Pi handling, stanniocalcin 1 was identified as an early response gene after foscarnet treatment; it was also regulated by extracellular Pi, and itself increased Pit1 accumulation in both osteoblast cultures and in vivo. These results provide new insights into the functional role of osteoblast autonomous Pi handling in normal bone mineralization and the abnormalities seen in skeletal tissue in hypophosphatemic disorders.

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