Dexamethasone and azathioprine promote cytoskeletal changes and affect mesenchymal stem cell migratory behavior

Glucocorticoids and immunosuppressive drugs are commonly used to treat inflammatory disorders, such as inflammatory bowel disease (IBD), and despite a few improvements, the remission of IBD is still difficult to maintain. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have e...

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Veröffentlicht in:PloS one 2015-03, Vol.10 (3), p.e0120538-e0120538
Hauptverfasser: Schneider, Natália, Gonçalves, Fabiany da Costa, Pinto, Fernanda Otesbelgue, Lopez, Patrícia Luciana da Costa, Araújo, Anelise Bergmann, Pfaffenseller, Bianca, Passos, Eduardo Pandolfi, Cirne-Lima, Elizabeth Obino, Meurer, Luíse, Lamers, Marcelo Lazzaron, Paz, Ana Helena
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container_issue 3
container_start_page e0120538
container_title PloS one
container_volume 10
creator Schneider, Natália
Gonçalves, Fabiany da Costa
Pinto, Fernanda Otesbelgue
Lopez, Patrícia Luciana da Costa
Araújo, Anelise Bergmann
Pfaffenseller, Bianca
Passos, Eduardo Pandolfi
Cirne-Lima, Elizabeth Obino
Meurer, Luíse
Lamers, Marcelo Lazzaron
Paz, Ana Helena
description Glucocorticoids and immunosuppressive drugs are commonly used to treat inflammatory disorders, such as inflammatory bowel disease (IBD), and despite a few improvements, the remission of IBD is still difficult to maintain. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have emerged as regulators of the immune response, and their viability and activation of their migratory properties are essential for successful cell therapy. However, little is known about the effects of immunosuppressant drugs used in IBD treatment on MSC behavior. The aim of this study was to evaluate MSC viability, nuclear morphometry, cell polarity, F-actin and focal adhesion kinase (FAK) distribution, and cell migratory properties in the presence of the immunosuppressive drugs azathioprine (AZA) and dexamethasone (DEX). After an initial characterization, MSCs were treated with DEX (10 μM) or AZA (1 μM) for 24 hrs or 7 days. Neither drug had an effect on cell viability or nuclear morphometry. However, AZA treatment induced a more elongated cell shape, while DEX was associated with a more rounded cell shape (P < 0.05) with a higher presence of ventral actin stress fibers (P < 0.05) and a decrease in protrusion stability. After 7 days of treatment, AZA improved the cell spatial trajectory (ST) and increased the migration speed (24.35%, P < 0.05, n = 4), while DEX impaired ST and migration speed after 24 hrs and 7 days of treatment (-28.69% and -25.37%, respectively; P < 0.05, n = 4). In conclusion, our data suggest that these immunosuppressive drugs each affect MSC morphology and migratory capacity differently, possibly impacting the success of cell therapy.
doi_str_mv 10.1371/journal.pone.0120538
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Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have emerged as regulators of the immune response, and their viability and activation of their migratory properties are essential for successful cell therapy. However, little is known about the effects of immunosuppressant drugs used in IBD treatment on MSC behavior. The aim of this study was to evaluate MSC viability, nuclear morphometry, cell polarity, F-actin and focal adhesion kinase (FAK) distribution, and cell migratory properties in the presence of the immunosuppressive drugs azathioprine (AZA) and dexamethasone (DEX). After an initial characterization, MSCs were treated with DEX (10 μM) or AZA (1 μM) for 24 hrs or 7 days. Neither drug had an effect on cell viability or nuclear morphometry. However, AZA treatment induced a more elongated cell shape, while DEX was associated with a more rounded cell shape (P &lt; 0.05) with a higher presence of ventral actin stress fibers (P &lt; 0.05) and a decrease in protrusion stability. After 7 days of treatment, AZA improved the cell spatial trajectory (ST) and increased the migration speed (24.35%, P &lt; 0.05, n = 4), while DEX impaired ST and migration speed after 24 hrs and 7 days of treatment (-28.69% and -25.37%, respectively; P &lt; 0.05, n = 4). In conclusion, our data suggest that these immunosuppressive drugs each affect MSC morphology and migratory capacity differently, possibly impacting the success of cell therapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120538</identifier><identifier>PMID: 25756665</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Actin ; Adhesion tests ; Azathioprine ; Azathioprine - pharmacology ; Bone marrow ; Care and treatment ; Cell adhesion &amp; migration ; Cell migration ; Cell Movement - drug effects ; Cell Shape - drug effects ; Cell size ; Cell Survival ; Cells, Cultured ; Cytokines ; Cytology ; Cytoskeleton ; Cytoskeleton - metabolism ; Dexamethasone ; Dexamethasone - pharmacology ; Dosage and administration ; Drug Evaluation, Preclinical ; Drugs ; Elongation ; Embryology ; Fibers ; Focal adhesion kinase ; Focal Adhesion Kinase 1 - metabolism ; Gastroenterology ; Gastrointestinal diseases ; Glucocorticoids ; Hepatology ; Humans ; Immune response ; Immune system ; Immunomodulation ; Immunosuppressive agents ; Immunosuppressive Agents - pharmacology ; Inflammation ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Inflammatory diseases ; Intestine ; Kinases ; Laboratories ; Mesenchymal stem cells ; Mesenchymal Stromal Cells - physiology ; Mesenchyme ; Morphology ; Morphometry ; Physiological aspects ; Polarity ; Properties (attributes) ; Regulators ; Remission ; Signal transduction ; Spatial distribution ; Stem cells ; Steroids ; Therapy</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0120538-e0120538</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Schneider et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Schneider et al 2015 Schneider et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-176b713e39cb2553032b407dc05af8d2047780e81d2f69fb6444f0a3f37b74283</citedby><cites>FETCH-LOGICAL-c758t-176b713e39cb2553032b407dc05af8d2047780e81d2f69fb6444f0a3f37b74283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355407/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355407/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25756665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Genetos, Damian Christopher</contributor><creatorcontrib>Schneider, Natália</creatorcontrib><creatorcontrib>Gonçalves, Fabiany da Costa</creatorcontrib><creatorcontrib>Pinto, Fernanda Otesbelgue</creatorcontrib><creatorcontrib>Lopez, Patrícia Luciana da Costa</creatorcontrib><creatorcontrib>Araújo, Anelise Bergmann</creatorcontrib><creatorcontrib>Pfaffenseller, Bianca</creatorcontrib><creatorcontrib>Passos, Eduardo Pandolfi</creatorcontrib><creatorcontrib>Cirne-Lima, Elizabeth Obino</creatorcontrib><creatorcontrib>Meurer, Luíse</creatorcontrib><creatorcontrib>Lamers, Marcelo Lazzaron</creatorcontrib><creatorcontrib>Paz, Ana Helena</creatorcontrib><title>Dexamethasone and azathioprine promote cytoskeletal changes and affect mesenchymal stem cell migratory behavior</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Glucocorticoids and immunosuppressive drugs are commonly used to treat inflammatory disorders, such as inflammatory bowel disease (IBD), and despite a few improvements, the remission of IBD is still difficult to maintain. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have emerged as regulators of the immune response, and their viability and activation of their migratory properties are essential for successful cell therapy. However, little is known about the effects of immunosuppressant drugs used in IBD treatment on MSC behavior. The aim of this study was to evaluate MSC viability, nuclear morphometry, cell polarity, F-actin and focal adhesion kinase (FAK) distribution, and cell migratory properties in the presence of the immunosuppressive drugs azathioprine (AZA) and dexamethasone (DEX). After an initial characterization, MSCs were treated with DEX (10 μM) or AZA (1 μM) for 24 hrs or 7 days. Neither drug had an effect on cell viability or nuclear morphometry. However, AZA treatment induced a more elongated cell shape, while DEX was associated with a more rounded cell shape (P &lt; 0.05) with a higher presence of ventral actin stress fibers (P &lt; 0.05) and a decrease in protrusion stability. After 7 days of treatment, AZA improved the cell spatial trajectory (ST) and increased the migration speed (24.35%, P &lt; 0.05, n = 4), while DEX impaired ST and migration speed after 24 hrs and 7 days of treatment (-28.69% and -25.37%, respectively; P &lt; 0.05, n = 4). In conclusion, our data suggest that these immunosuppressive drugs each affect MSC morphology and migratory capacity differently, possibly impacting the success of cell therapy.</description><subject>Actin</subject><subject>Adhesion tests</subject><subject>Azathioprine</subject><subject>Azathioprine - pharmacology</subject><subject>Bone marrow</subject><subject>Care and treatment</subject><subject>Cell adhesion &amp; migration</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell Shape - drug effects</subject><subject>Cell size</subject><subject>Cell Survival</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Cytology</subject><subject>Cytoskeleton</subject><subject>Cytoskeleton - metabolism</subject><subject>Dexamethasone</subject><subject>Dexamethasone - pharmacology</subject><subject>Dosage and administration</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drugs</subject><subject>Elongation</subject><subject>Embryology</subject><subject>Fibers</subject><subject>Focal adhesion kinase</subject><subject>Focal Adhesion Kinase 1 - metabolism</subject><subject>Gastroenterology</subject><subject>Gastrointestinal diseases</subject><subject>Glucocorticoids</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunomodulation</subject><subject>Immunosuppressive agents</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory bowel diseases</subject><subject>Inflammatory diseases</subject><subject>Intestine</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stromal Cells - physiology</subject><subject>Mesenchyme</subject><subject>Morphology</subject><subject>Morphometry</subject><subject>Physiological aspects</subject><subject>Polarity</subject><subject>Properties (attributes)</subject><subject>Regulators</subject><subject>Remission</subject><subject>Signal transduction</subject><subject>Spatial distribution</subject><subject>Stem 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Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schneider, Natália</au><au>Gonçalves, Fabiany da Costa</au><au>Pinto, Fernanda Otesbelgue</au><au>Lopez, Patrícia Luciana da Costa</au><au>Araújo, Anelise Bergmann</au><au>Pfaffenseller, Bianca</au><au>Passos, Eduardo Pandolfi</au><au>Cirne-Lima, Elizabeth Obino</au><au>Meurer, Luíse</au><au>Lamers, Marcelo Lazzaron</au><au>Paz, Ana Helena</au><au>Genetos, Damian Christopher</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dexamethasone and azathioprine promote cytoskeletal changes and affect mesenchymal stem cell migratory behavior</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-10</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0120538</spage><epage>e0120538</epage><pages>e0120538-e0120538</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Glucocorticoids and immunosuppressive drugs are commonly used to treat inflammatory disorders, such as inflammatory bowel disease (IBD), and despite a few improvements, the remission of IBD is still difficult to maintain. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have emerged as regulators of the immune response, and their viability and activation of their migratory properties are essential for successful cell therapy. However, little is known about the effects of immunosuppressant drugs used in IBD treatment on MSC behavior. The aim of this study was to evaluate MSC viability, nuclear morphometry, cell polarity, F-actin and focal adhesion kinase (FAK) distribution, and cell migratory properties in the presence of the immunosuppressive drugs azathioprine (AZA) and dexamethasone (DEX). After an initial characterization, MSCs were treated with DEX (10 μM) or AZA (1 μM) for 24 hrs or 7 days. Neither drug had an effect on cell viability or nuclear morphometry. However, AZA treatment induced a more elongated cell shape, while DEX was associated with a more rounded cell shape (P &lt; 0.05) with a higher presence of ventral actin stress fibers (P &lt; 0.05) and a decrease in protrusion stability. After 7 days of treatment, AZA improved the cell spatial trajectory (ST) and increased the migration speed (24.35%, P &lt; 0.05, n = 4), while DEX impaired ST and migration speed after 24 hrs and 7 days of treatment (-28.69% and -25.37%, respectively; P &lt; 0.05, n = 4). In conclusion, our data suggest that these immunosuppressive drugs each affect MSC morphology and migratory capacity differently, possibly impacting the success of cell therapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25756665</pmid><doi>10.1371/journal.pone.0120538</doi><oa>free_for_read</oa></addata></record>
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1932-6203
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subjects Actin
Adhesion tests
Azathioprine
Azathioprine - pharmacology
Bone marrow
Care and treatment
Cell adhesion & migration
Cell migration
Cell Movement - drug effects
Cell Shape - drug effects
Cell size
Cell Survival
Cells, Cultured
Cytokines
Cytology
Cytoskeleton
Cytoskeleton - metabolism
Dexamethasone
Dexamethasone - pharmacology
Dosage and administration
Drug Evaluation, Preclinical
Drugs
Elongation
Embryology
Fibers
Focal adhesion kinase
Focal Adhesion Kinase 1 - metabolism
Gastroenterology
Gastrointestinal diseases
Glucocorticoids
Hepatology
Humans
Immune response
Immune system
Immunomodulation
Immunosuppressive agents
Immunosuppressive Agents - pharmacology
Inflammation
Inflammatory bowel disease
Inflammatory bowel diseases
Inflammatory diseases
Intestine
Kinases
Laboratories
Mesenchymal stem cells
Mesenchymal Stromal Cells - physiology
Mesenchyme
Morphology
Morphometry
Physiological aspects
Polarity
Properties (attributes)
Regulators
Remission
Signal transduction
Spatial distribution
Stem cells
Steroids
Therapy
title Dexamethasone and azathioprine promote cytoskeletal changes and affect mesenchymal stem cell migratory behavior
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