Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy
[Display omitted] Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel con...
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| Veröffentlicht in: | Acta biomaterialia 2018-04, Vol.70, p.71-83 |
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| creator | Ciuffreda, Maria Chiara Malpasso, Giuseppe Chokoza, Cindy Bezuidenhout, Deon Goetsch, Kyle P. Mura, Manuela Pisano, Federica Davies, Neil H. Gnecchi, Massimiliano |
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Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy.
In vitro, rat bone-marrow MSC (rBM-MSC) were seeded and grown into H-HG. Under normoxia, the hydrogel did not affect cell survival (rBM-MSC survival >90% at each time point tested); vice versa, under hypoxia the biomaterial resulted to be protective for the cells (p |
| doi_str_mv | 10.1016/j.actbio.2018.01.005 |
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Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy.
In vitro, rat bone-marrow MSC (rBM-MSC) were seeded and grown into H-HG. Under normoxia, the hydrogel did not affect cell survival (rBM-MSC survival >90% at each time point tested); vice versa, under hypoxia the biomaterial resulted to be protective for the cells (p < .001 vs rBM-MSC alone).
H-HG or control PEG hydrogels (HG) were incubated with VEGF or bFGF for binding/release quantification. Data showed significantly higher amount of VEGF and bFGF bound by H-HG compared with HG (p < .05) and a constant release over time.
In vivo, myocardial infarction (MI) was induced in female Sprague Dawley rats by permanent coronary ligation. One week later, saline, rBM-MSC, H-HG or rBM-MSC/H-HG were injected in the infarct zone. The co-injection of rBM-MSC/H-HG into infarcted hearts significantly increased cardiac function. Importantly, we observed a significant gain in MSC engraftment, reduction of ventricular remodeling and stimulation of neo-vasculogenesis. We also documented higher amounts of several pro-angiogenic factors in hearts treated with rBM-MSC/H-HG.
Our data show that H-HG increases MSC engraftment, efficiently fine tunes the paracrine MSC actions and improves cardiac function in infarcted rat hearts.
Transplantation of MSC is a promising treatment for ischemic heart disease, but low cell engraftment has so far limited its efficacy. The enzymatically degradable H-HG that we developed is able to increase MSC retention/engraftment and, at the same time, to fine-tune the paracrine effects mediated by the cells. Most importantly, the co-transplantation of MSC and H-HG in a rat model of ischemic cardiomyopathy improved heart function through a significant reduction in ventricular remodeling/scarring and amelioration in neo-vasculogenesis/endogenous cardiac regeneration. These beneficial effects are comparable to those obtained by others using a much greater number of cells, strengthening the efficacy of the biomaterial used in increasing the therapeutic effects of MSC. Given its efficacy and safety, documented by the absence of immunoreaction, our strategy appears readily translatable to clinical scenarios.</description><identifier>ISSN: 1742-7061</identifier><identifier>EISSN: 1878-7568</identifier><identifier>DOI: 10.1016/j.actbio.2018.01.005</identifier><identifier>PMID: 29341932</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Angiogenesis ; Animals ; Binding ; Biomaterial ; Biomaterials ; Biomedical materials ; Biomimetic Materials - chemistry ; Bone marrow ; Bone Marrow Cells - metabolism ; Bone Marrow Cells - pathology ; Cardiomyopathy ; Cell survival ; Cells, Immobilized - metabolism ; Cells, Immobilized - pathology ; Cells, Immobilized - transplantation ; Coinjection ; Effectiveness ; Extracellular matrix ; Extracellular Matrix - chemistry ; Fibroblast growth factor 2 ; Heart ; Heart attacks ; Heparin ; Hydrogel ; Hydrogels ; Hydrogels - chemistry ; Hypoxia ; In vitro methods and tests ; Ischemia ; Male ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells - metabolism ; Mesenchymal Stem Cells - pathology ; Mesenchymal stromal cells ; Mesenchyme ; Myocardial infarction ; Myocardial Ischemia - metabolism ; Myocardial Ischemia - pathology ; Myocardial Ischemia - therapy ; Paracrine effect ; Paracrine signalling ; Rats ; Rats, Sprague-Dawley ; Stromal cells ; Survival ; Therapy ; Vascular endothelial growth factor ; Ventricle</subject><ispartof>Acta biomaterialia, 2018-04, Vol.70, p.71-83</ispartof><rights>2018 Acta Materialia Inc.</rights><rights>Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier BV Apr 1, 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-c1f6f30623b66498fbbb61157b9f44f4a80ec3c4532ea1e6ac7c71ae22a8d4d63</citedby><cites>FETCH-LOGICAL-c427t-c1f6f30623b66498fbbb61157b9f44f4a80ec3c4532ea1e6ac7c71ae22a8d4d63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.actbio.2018.01.005$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29341932$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ciuffreda, Maria Chiara</creatorcontrib><creatorcontrib>Malpasso, Giuseppe</creatorcontrib><creatorcontrib>Chokoza, Cindy</creatorcontrib><creatorcontrib>Bezuidenhout, Deon</creatorcontrib><creatorcontrib>Goetsch, Kyle P.</creatorcontrib><creatorcontrib>Mura, Manuela</creatorcontrib><creatorcontrib>Pisano, Federica</creatorcontrib><creatorcontrib>Davies, Neil H.</creatorcontrib><creatorcontrib>Gnecchi, Massimiliano</creatorcontrib><title>Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy</title><title>Acta biomaterialia</title><addtitle>Acta Biomater</addtitle><description>[Display omitted]
Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy.
In vitro, rat bone-marrow MSC (rBM-MSC) were seeded and grown into H-HG. Under normoxia, the hydrogel did not affect cell survival (rBM-MSC survival >90% at each time point tested); vice versa, under hypoxia the biomaterial resulted to be protective for the cells (p < .001 vs rBM-MSC alone).
H-HG or control PEG hydrogels (HG) were incubated with VEGF or bFGF for binding/release quantification. Data showed significantly higher amount of VEGF and bFGF bound by H-HG compared with HG (p < .05) and a constant release over time.
In vivo, myocardial infarction (MI) was induced in female Sprague Dawley rats by permanent coronary ligation. One week later, saline, rBM-MSC, H-HG or rBM-MSC/H-HG were injected in the infarct zone. The co-injection of rBM-MSC/H-HG into infarcted hearts significantly increased cardiac function. Importantly, we observed a significant gain in MSC engraftment, reduction of ventricular remodeling and stimulation of neo-vasculogenesis. We also documented higher amounts of several pro-angiogenic factors in hearts treated with rBM-MSC/H-HG.
Our data show that H-HG increases MSC engraftment, efficiently fine tunes the paracrine MSC actions and improves cardiac function in infarcted rat hearts.
Transplantation of MSC is a promising treatment for ischemic heart disease, but low cell engraftment has so far limited its efficacy. The enzymatically degradable H-HG that we developed is able to increase MSC retention/engraftment and, at the same time, to fine-tune the paracrine effects mediated by the cells. Most importantly, the co-transplantation of MSC and H-HG in a rat model of ischemic cardiomyopathy improved heart function through a significant reduction in ventricular remodeling/scarring and amelioration in neo-vasculogenesis/endogenous cardiac regeneration. These beneficial effects are comparable to those obtained by others using a much greater number of cells, strengthening the efficacy of the biomaterial used in increasing the therapeutic effects of MSC. Given its efficacy and safety, documented by the absence of immunoreaction, our strategy appears readily translatable to clinical scenarios.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Binding</subject><subject>Biomaterial</subject><subject>Biomaterials</subject><subject>Biomedical materials</subject><subject>Biomimetic Materials - chemistry</subject><subject>Bone marrow</subject><subject>Bone Marrow Cells - metabolism</subject><subject>Bone Marrow Cells - pathology</subject><subject>Cardiomyopathy</subject><subject>Cell survival</subject><subject>Cells, Immobilized - metabolism</subject><subject>Cells, Immobilized - pathology</subject><subject>Cells, Immobilized - transplantation</subject><subject>Coinjection</subject><subject>Effectiveness</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - chemistry</subject><subject>Fibroblast growth factor 2</subject><subject>Heart</subject><subject>Heart attacks</subject><subject>Heparin</subject><subject>Hydrogel</subject><subject>Hydrogels</subject><subject>Hydrogels - chemistry</subject><subject>Hypoxia</subject><subject>In vitro methods and tests</subject><subject>Ischemia</subject><subject>Male</subject><subject>Mesenchymal Stem Cell Transplantation</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchymal Stem Cells - pathology</subject><subject>Mesenchymal stromal cells</subject><subject>Mesenchyme</subject><subject>Myocardial infarction</subject><subject>Myocardial Ischemia - metabolism</subject><subject>Myocardial Ischemia - pathology</subject><subject>Myocardial Ischemia - therapy</subject><subject>Paracrine effect</subject><subject>Paracrine signalling</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Stromal cells</subject><subject>Survival</subject><subject>Therapy</subject><subject>Vascular endothelial growth factor</subject><subject>Ventricle</subject><issn>1742-7061</issn><issn>1878-7568</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU-L1TAUxYMozjj6DUQCbty0JmmaJhtBhvEPDLhQ1yFNb2wezcszSYfpyq9uyhtduHB1L9zfPfdwD0IvKWkpoeLtoTW2jD62jFDZEtoS0j9Cl1QOshl6IR_XfuCsGYigF-hZzgdCOkmZfIoumOo4VR27RL--bscyQ_EWw31JxsKyrItJOJiS_D0OPtTRvE0p_oAF-3BK8Q4yBue8NXbD0eEAGY523oJZcC4p7nXXwVU4mdOGXUzYZzvDrmVNmnwMWzyZMm_P0RNnlgwvHuoV-v7h5tv1p-b2y8fP1-9vG8vZUBpLnXAdEawbheBKunEcBaX9MCrHueNGErCd5X3HwFAQxg52oAYYM3Lik-iu0JuzbvX_c4VcdKiOqklzhLhmTZVUvRSKyIq-_gc9xDUdqzvNiFA9oapnleJnyqaYcwKnT8kHkzZNid4D0gd9DkjvAWlCdQ2orr16EF_HANPfpT-JVODdGYD6jTsPSWfr63th8gls0VP0_7_wG3Eapos</recordid><startdate>20180401</startdate><enddate>20180401</enddate><creator>Ciuffreda, Maria Chiara</creator><creator>Malpasso, Giuseppe</creator><creator>Chokoza, Cindy</creator><creator>Bezuidenhout, Deon</creator><creator>Goetsch, Kyle P.</creator><creator>Mura, Manuela</creator><creator>Pisano, Federica</creator><creator>Davies, Neil H.</creator><creator>Gnecchi, Massimiliano</creator><general>Elsevier Ltd</general><general>Elsevier BV</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QO</scope><scope>7QQ</scope><scope>7SC</scope><scope>7SE</scope><scope>7SP</scope><scope>7SR</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>JG9</scope><scope>JQ2</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20180401</creationdate><title>Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy</title><author>Ciuffreda, Maria Chiara ; Malpasso, Giuseppe ; Chokoza, Cindy ; Bezuidenhout, Deon ; Goetsch, Kyle P. ; Mura, Manuela ; Pisano, Federica ; Davies, Neil H. ; Gnecchi, Massimiliano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-c1f6f30623b66498fbbb61157b9f44f4a80ec3c4532ea1e6ac7c71ae22a8d4d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Binding</topic><topic>Biomaterial</topic><topic>Biomaterials</topic><topic>Biomedical materials</topic><topic>Biomimetic Materials - chemistry</topic><topic>Bone marrow</topic><topic>Bone Marrow Cells - metabolism</topic><topic>Bone Marrow Cells - pathology</topic><topic>Cardiomyopathy</topic><topic>Cell survival</topic><topic>Cells, Immobilized - metabolism</topic><topic>Cells, Immobilized - pathology</topic><topic>Cells, Immobilized - transplantation</topic><topic>Coinjection</topic><topic>Effectiveness</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix - chemistry</topic><topic>Fibroblast growth factor 2</topic><topic>Heart</topic><topic>Heart attacks</topic><topic>Heparin</topic><topic>Hydrogel</topic><topic>Hydrogels</topic><topic>Hydrogels - chemistry</topic><topic>Hypoxia</topic><topic>In vitro methods and tests</topic><topic>Ischemia</topic><topic>Male</topic><topic>Mesenchymal Stem Cell Transplantation</topic><topic>Mesenchymal Stem Cells - metabolism</topic><topic>Mesenchymal Stem Cells - pathology</topic><topic>Mesenchymal stromal cells</topic><topic>Mesenchyme</topic><topic>Myocardial infarction</topic><topic>Myocardial Ischemia - metabolism</topic><topic>Myocardial Ischemia - pathology</topic><topic>Myocardial Ischemia - therapy</topic><topic>Paracrine effect</topic><topic>Paracrine signalling</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Stromal cells</topic><topic>Survival</topic><topic>Therapy</topic><topic>Vascular endothelial growth factor</topic><topic>Ventricle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ciuffreda, Maria Chiara</creatorcontrib><creatorcontrib>Malpasso, Giuseppe</creatorcontrib><creatorcontrib>Chokoza, Cindy</creatorcontrib><creatorcontrib>Bezuidenhout, Deon</creatorcontrib><creatorcontrib>Goetsch, Kyle P.</creatorcontrib><creatorcontrib>Mura, Manuela</creatorcontrib><creatorcontrib>Pisano, Federica</creatorcontrib><creatorcontrib>Davies, Neil H.</creatorcontrib><creatorcontrib>Gnecchi, Massimiliano</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Acta biomaterialia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ciuffreda, Maria Chiara</au><au>Malpasso, Giuseppe</au><au>Chokoza, Cindy</au><au>Bezuidenhout, Deon</au><au>Goetsch, Kyle P.</au><au>Mura, Manuela</au><au>Pisano, Federica</au><au>Davies, Neil H.</au><au>Gnecchi, Massimiliano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy</atitle><jtitle>Acta biomaterialia</jtitle><addtitle>Acta Biomater</addtitle><date>2018-04-01</date><risdate>2018</risdate><volume>70</volume><spage>71</spage><epage>83</epage><pages>71-83</pages><issn>1742-7061</issn><eissn>1878-7568</eissn><abstract>[Display omitted]
Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy.
In vitro, rat bone-marrow MSC (rBM-MSC) were seeded and grown into H-HG. Under normoxia, the hydrogel did not affect cell survival (rBM-MSC survival >90% at each time point tested); vice versa, under hypoxia the biomaterial resulted to be protective for the cells (p < .001 vs rBM-MSC alone).
H-HG or control PEG hydrogels (HG) were incubated with VEGF or bFGF for binding/release quantification. Data showed significantly higher amount of VEGF and bFGF bound by H-HG compared with HG (p < .05) and a constant release over time.
In vivo, myocardial infarction (MI) was induced in female Sprague Dawley rats by permanent coronary ligation. One week later, saline, rBM-MSC, H-HG or rBM-MSC/H-HG were injected in the infarct zone. The co-injection of rBM-MSC/H-HG into infarcted hearts significantly increased cardiac function. Importantly, we observed a significant gain in MSC engraftment, reduction of ventricular remodeling and stimulation of neo-vasculogenesis. We also documented higher amounts of several pro-angiogenic factors in hearts treated with rBM-MSC/H-HG.
Our data show that H-HG increases MSC engraftment, efficiently fine tunes the paracrine MSC actions and improves cardiac function in infarcted rat hearts.
Transplantation of MSC is a promising treatment for ischemic heart disease, but low cell engraftment has so far limited its efficacy. The enzymatically degradable H-HG that we developed is able to increase MSC retention/engraftment and, at the same time, to fine-tune the paracrine effects mediated by the cells. Most importantly, the co-transplantation of MSC and H-HG in a rat model of ischemic cardiomyopathy improved heart function through a significant reduction in ventricular remodeling/scarring and amelioration in neo-vasculogenesis/endogenous cardiac regeneration. These beneficial effects are comparable to those obtained by others using a much greater number of cells, strengthening the efficacy of the biomaterial used in increasing the therapeutic effects of MSC. Given its efficacy and safety, documented by the absence of immunoreaction, our strategy appears readily translatable to clinical scenarios.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29341932</pmid><doi>10.1016/j.actbio.2018.01.005</doi><tpages>13</tpages></addata></record> |
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| ispartof | Acta biomaterialia, 2018-04, Vol.70, p.71-83 |
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| subjects | Angiogenesis Animals Binding Biomaterial Biomaterials Biomedical materials Biomimetic Materials - chemistry Bone marrow Bone Marrow Cells - metabolism Bone Marrow Cells - pathology Cardiomyopathy Cell survival Cells, Immobilized - metabolism Cells, Immobilized - pathology Cells, Immobilized - transplantation Coinjection Effectiveness Extracellular matrix Extracellular Matrix - chemistry Fibroblast growth factor 2 Heart Heart attacks Heparin Hydrogel Hydrogels Hydrogels - chemistry Hypoxia In vitro methods and tests Ischemia Male Mesenchymal Stem Cell Transplantation Mesenchymal Stem Cells - metabolism Mesenchymal Stem Cells - pathology Mesenchymal stromal cells Mesenchyme Myocardial infarction Myocardial Ischemia - metabolism Myocardial Ischemia - pathology Myocardial Ischemia - therapy Paracrine effect Paracrine signalling Rats Rats, Sprague-Dawley Stromal cells Survival Therapy Vascular endothelial growth factor Ventricle |
| title | Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy |
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