A developmental analysis of oligodendroglial integrins in primary cells: changes in alpha v-associated beta subunits during differentiation

Development ◽  
1994 ◽  
Vol 120 (12) ◽  
pp. 3497-3506 ◽  
Author(s):  
R. Milner ◽  
C. Ffrench-Constant
Keyword(s):  
Progenitor Cell ◽  
Beta Subunits ◽  
Integrin Expression ◽  
Primary Cells ◽  
Developmentally Regulated ◽  
Rgd Peptides ◽  
Rational Explanation ◽  
Oligodendrocyte Precursor ◽  
Alpha V Beta 3 ◽  
Developmental Analysis

We have examined the expression of integrins on primary oligodendroglial cells during the differentiation of the proliferative oligodendrocyte precursor (O-2A progenitor) cell to the postmitotic oligodendrocyte. Cells of the oligodendrocyte lineage expressed a limited repertoire of integrins: alpha 6 beta 1 and alpha v integrins including alpha v beta 1, alpha v beta 3 and alpha v beta 5, as well as a potentially novel integrin alpha v beta 80 kDa. Integrin expression was developmentally regulated; during differentiation alpha v beta 1 was reduced and alpha v beta 5 upregulated. These results suggest that laminin and vitronectin are important extracellular matrix ligands for oligodendrocytes, and provide a rational explanation for previous observations that RGD peptides inhibit the expression of myelin-specific genes. They also suggest a simple model by which switching of integrin beta subunits might regulate differentiation. As chimeric beta 1 integrins with a beta 5 cytoplasmic domain support proliferation less well than normal beta 1 integrins (Pasqualini and Hemler (1994), J. Cell Biol. 125, 447–460) the switch from alpha v beta 1 to alpha v beta 5 might play a key instructive role in the cessation of proliferation and subsequent differentiation.

scholarly journals Isolation of a highly specific ligand for the alpha 5 beta 1 integrin from a phage display library

1994 ◽  
Vol 124 (3) ◽  
pp. 373-380 ◽  
Author(s):  
E Koivunen ◽  
B Wang ◽  
E Ruoslahti
Keyword(s):  
Phage Display ◽  
Cyclic Peptide ◽  
Cell Attachment ◽  
Phage Display Library ◽  
Cell Binding ◽  
Rgd Peptides ◽  
Beta 1 Integrin ◽  
Alpha V Beta 3 ◽  
Integrin Ligand ◽  
Specific Ligand

Our previous studies showed that the alpha 5 beta 1 integrin selects cysteine pair-containing RGD peptides from a phage display library based on a random hexapeptide. We have therefore searched for more selective peptides for this integrin using a larger phage display library, where heptapeptides are flanked by cysteine residues, thus making the inserts potentially cyclic. Most of the phage sequences that bound to alpha 5 beta 1 (69 of 125) contained the RGD motif. Some of the heptapeptides contained an NGR motif. As the NGR sequence occurs in the cell-binding region of the fibronectin molecule, this sequence could contribute to the specific recognition of fibronectin by alpha 5 beta 1. Selection for high affinity peptides for alpha 5 beta 1 surprisingly yielded a sequence RRETAWA that does not bear obvious resemblance to known integrin ligand sequences. The synthetic cyclic peptide GACRRETAWACGA (*CRRETAWAC*) was a potent inhibitor of alpha 5 beta 1-mediated cell attachment to fibronectin. This peptide is nearly specific for the alpha 5 beta 1 integrin, because much higher concentrations were needed to inhibit the alpha v beta 1 integrin, and there was no effect on alpha v beta 3- and alpha v beta 5-mediated cell attachment to vitronectin. The peptide also did not bind to the alpha IIb beta 3 integrin. *CRRETAWAC* appears to interact with the same or an overlapping binding site in alpha 5 beta 1 as RGD, because cell attachment to *CRRETAWAC* coated on plastic was divalent cation dependent and could be blocked by an RGD-containing peptide. These results reveal a novel binding specificity in the alpha 5 beta 1 integrin.

scholarly journals Distinct progenitor behavior underlying neocortical gliogenesis related to tumorigenesis

2020 ◽  
Author(s):  
Zhongfu Shen ◽  
Yang Lin ◽  
Jiajun Yang ◽  
David J. Jörg ◽  
Yuwei Peng ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Neurofibromatosis Type ◽  
Primary Brain Tumor ◽  
Precursor Cells ◽  
Cell Behavior ◽  
Neocortical Neurons ◽  
Glial Progenitors ◽  
Radial Glial ◽  
Oligodendrocyte Precursor

SUMMARYRadial glial progenitors (RGPs) are responsible for producing the vast majority of neurons and glia in the neocortex. While RGP behavior and progressive generation of neocortical neurons have been delineated, the exact process of neocortical gliogenesis remains elusive. Here, we report the precise progenitor cell behavior and gliogenesis program at single-cell resolution in the mouse neocortex. RGPs transition from neurogenesis to gliogenesis progressively, producing astrocytes, oligodendrocytes, or both in well-defined propensities of 60%:15%:25%, respectively, via fate-restricted “intermediate” precursor cells. While the total number of precursor cells generated by individual RGPs appears stochastic, the output of individual precursor cells exhibit clear patterns in number and subtype, and form discrete local subclusters. Clonal loss of tumor suppressor Neurofibromatosis type 1 leads to excessive production of glia selectively, especially oligodendrocyte precursor cells. These results delineate the cellular program of neocortical gliogenesis quantitatively and suggest the cellular and lineage origin of primary brain tumor.

scholarly journals Fibrinogen potentiates the effect of interleukin-3 on early human hematopoietic progenitors

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 800-806 ◽  
Author(s):  
YQ Zhou ◽  
JP Levesque ◽  
A Hatzfeld ◽  
AA Cardoso ◽  
ML Li ◽  
...  
Keyword(s):  
Dependent Manner ◽  
Mitogenic Effect ◽  
Hematopoietic Progenitors ◽  
Human Fibrinogen ◽  
Rgd Peptides ◽  
Interleukin 3 ◽  
Fibrinogen Binding ◽  
Clonal Cultures ◽  
Beta 2 ◽  
Alpha V Beta 3

Abstract The effect of human fibrinogen on the proliferation of purified SBA- CD34+ human bone marrow progenitors was investigated in clonal cultures. Fibrinogen alone or in combination with erythropoietin had no significant effect. However, in the presence of recombinant human interleukin-3 (IL-3), fibrinogen increased significantly in a dose- dependent manner the number of mixed and burst-forming unit-ethrocyte-- derived colonies, whereas the number of other colonies did not significantly change. In the presence of fibrinogen, low concentrations of IL-3 (0.17 U/mL) produced three times more mixed colonies than without fibrinogen, reaching the number of colonies obtained with optimal concentrations of IL-3 (1.67 U/mL). Fibrinogen fragment D had the same effect in the presence of IL-3 as intact fibrinogen, whereas fibrinogen fragment E and human collagen IV did not. This effect was not mediated by integrins, because peptides or monoclonal antibodies that block fibrinogen binding on integrins alpha IIb beta 3, alpha v beta 3 (RGD-peptides), alpha m beta 2 (OKM-1), and alpha x beta 2 (HC1/1) did not affect the observed mitogenic effect. The mitogenic effect of fibrinogen and its D fragment was not mediated by induction of IL-6 or granulocyte--colony-stimulating factor secretion, because it was not inhibited by blocking antisera against these two growth factors. Our results indicate that fibrinogen potentiates the effect of IL-3 on primitive hematopoietic progenitors and suggest that the mitogenic effect of fibrinogen could be mediated via a specific mitogenic receptor that does not belong to the integrin family.

scholarly journals PET Radiopharmaceuticals for Imaging Integrin Expression: Tracers in Clinical Studies and Recent Developments

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Roland Haubner ◽  
Simone Maschauer ◽  
Olaf Prante
Keyword(s):  
Nuclear Medicine ◽  
First Generation ◽  
Integrin Expression ◽  
Rgd Peptides ◽  
Recent Developments ◽  
Interesting Approach ◽  
Complex Chemistry ◽  
Pet Radiopharmaceuticals

Noninvasive determination of integrin expression has become an interesting approach in nuclear medicine. Since the discovery of the first18F-labeled cyclic RGD peptide as radiotracer for imaging integrinαvβ3expression in vivo, there have been carried out enormous efforts to develop RGD peptides for PET imaging. Moreover, in recent years, additional integrins, includingα5β1andαvβ6, came into the focus of pharmaceutical radiochemistry. This review will discuss the tracers already evaluated in clinical trials and summarize the preliminary outcome. It will also give an overview on recent developments to further optimize the first-generation compounds such as [18F]Galacto-RGD. This includes recently developed18F-labeling strategies and also new approaches in68Ga-complex chemistry. Furthermore, the approaches to develop radiopharmaceuticals targeting integrinα5β1andαvβ6will be summarized and discussed.

scholarly journals In vivo alpha-V beta-3 integrin expression in human aortic atherosclerosis

Heart ◽  
2019 ◽  
Vol 105 (24) ◽  
pp. 1868-1875 ◽  
Author(s):  
William S Jenkins ◽  
Alex T Vesey ◽  
Anna Vickers ◽  
Anoushka Neale ◽  
Catriona Moles ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Wall Thickness ◽  
Kinetic Modelling ◽  
Integrin Expression ◽  
Aortic Atherosclerosis ◽  
Plaque Volume ◽  
Recent Myocardial Infarction ◽  
Atherosclerotic Burden ◽  
Alpha V Beta 3

ObjectivesIntraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvβ3) integrin pathway. We investigated the applicability of the αvβ3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis.MethodsVascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217–237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring.Results18F-Fluciclatide uptake co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02).ConclusionsIn vivo expression of αvβ3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvβ3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.

Differential regulation of epaxial and hypaxial muscle development by paraxis

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5217-5229 ◽  
Author(s):  
J. Wilson-Rawls ◽  
C.R. Hurt ◽  
S.M. Parsons ◽  
A. Rawls
Keyword(s):  
Progenitor Cell ◽  
Muscle Development ◽  
Trunk Muscles ◽  
Developmentally Regulated ◽  
Myogenic Lineage ◽  
Important Regulator ◽  
Myogenic Factor ◽  
Myogenic Progenitor Cells ◽  
Different Origins ◽  
Myod Expression

In vertebrates, skeletal muscle is derived from progenitor cell populations located in the epithelial dermomyotome compartment of the each somite. These cells become committed to the myogenic lineage upon delamination from the dorsomedial and dorsolateral lips of the dermomyotome and entry into the myotome or dispersal into the periphery. Paraxis is a developmentally regulated transcription factor that is required to direct and maintain the epithelial characteristic of the dermomyotome. Therefore, we hypothesized that Paraxis acts as an important regulator of early events in myogenesis. Expression of the muscle-specific myogenin-lacZ transgene was used to examine the formation of the myotome in the paraxis−/− background. Two distinct types of defects were observed that mirrored the different origins of myoblasts in the myotome. In the medial myotome, where the expression of the myogenic factor Myf5 is required for commitment of myoblasts, the migration pattern of committed myoblasts was altered in the absence of Paraxis. In contrast, in the lateral myotome and migratory somitic cells, which require the expression of MyoD, expression of the myogenin-lacZ transgene was delayed by several days. This delay correlated with an absence of MyoD expression in these regions, indicating that Paraxis is required for commitment of cells from the dorsolateral dermomyotome to the myogenic lineage. In paraxis−/−/myf5−/− neonates, dramatic losses were observed in the epaxial and hypaxial trunk muscles that are proximal to the vertebrae in the compound mutant, but not those at the ventral midline or the non-segmented muscles of the limb and tongue. In this genetic background, myoblasts derived from the medial (epaxial) myotome are not present to compensate for deficiencies of the lateral (hypaxial) myotome. Our data demonstrate that Paraxis is an important regulator of a subset of the myogenic progenitor cells from the dorsolateral dermomyotome that are fated to form the non-migratory hypaxial muscles.

scholarly journals Affinity modulation of the alpha IIb beta 3 integrin (platelet GPIIb-IIIa) is an intrinsic property of the receptor.

1990 ◽  
Vol 1 (12) ◽  
pp. 883-893 ◽  
Author(s):  
T E O'Toole ◽  
J C Loftus ◽  
X P Du ◽  
A A Glass ◽  
Z M Ruggeri ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Chinese Hamster ◽  
Intrinsic Property ◽  
Ovary Cell ◽  
Rgd Peptides ◽  
Peptide Recognition ◽  
Recombinant Receptors ◽  
Affinity Modulation ◽  
Alpha V Beta 3 ◽  
Papain Digestion

To analyze the basis of affinity modulation of integrin function, we studied cloned stable Chinese hamster ovary cell lines expressing recombinant integrins of the beta 3 family (alpha IIb beta 3 and alpha v beta 3). Antigenic and peptide recognition specificities of the recombinant receptors resembled those of the native receptors found in platelets or endothelial cells. The alpha IIb beta 3-expressing cell line (A5) bound RGD peptides and immobilized fibrinogen (Fg) but not soluble fibrinogen or the activation-specific monoclonal anti-alpha IIb beta 3 (PAC1), indicating that it was in the affinity state found on resting platelets. Several platelet agonists failed to alter the affinity state of ("activate") recombinant alpha IIb beta 3. The binding of soluble Fg and PAC1, however, was stimulated in both platelets and A5 cells by addition of IgG papain-digestion products (Fab) fragments of certain beta 3-specific monoclonal antibodies. These antibodies stimulated PAC1 binding to platelets fixed under conditions rendering them unresponsive to other agonists. Addition of these antibodies to detergent-solubilized alpha IIb beta 3 also stimulated specific Fg binding. These data demonstrate that certain anti-beta 3 antibodies activate alpha IIb beta 3 by acting directly on the receptor, possibly by altering its conformation. Furthermore, they indicate that the activation state of alpha IIb beta 3 is a property of the receptor itself rather than of the surrounding cell membrane microenvironment.

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