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Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling...
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| Published in: | PloS one 2016-01, Vol.11 (1), p.e0146697-e0146697 |
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| description | Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new in vitro model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease. |
| doi_str_mv | 10.1371/journal.pone.0146697 |
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HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new in vitro model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0146697</identifier><identifier>PMID: 26784941</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Atrial Natriuretic Factor - genetics ; Atrial Natriuretic Factor - metabolism ; Atrial natriuretic peptide ; Biomedical materials ; Cardiac arrhythmia ; Cardiomyocytes ; Cardiomyopathy ; Cardiomyopathy, Hypertrophic - genetics ; Cardiomyopathy, Hypertrophic - physiopathology ; Cell culture ; Cell cycle ; Cell Differentiation ; Cells, Cultured ; Childrens health ; Chlorofluorocarbons ; Contraction ; Coronary artery disease ; Development and progression ; Equipment and supplies ; Gene expression ; Genetic disorders ; Health aspects ; Heart ; Heart diseases ; Human subjects ; Humans ; Hypertrophic cardiomyopathy ; Induced Pluripotent Stem Cells - cytology ; Induced Pluripotent Stem Cells - metabolism ; Kinases ; MAP kinase ; Medicine ; Methods ; Mutation ; Myocardial Contraction ; Myocytes ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - physiology ; Patients ; Pluripotency ; Principal components analysis ; Proto-Oncogene Proteins B-raf - genetics ; Rodents ; Signaling ; Stem cells ; Stiffness ; Substrates ; Three dimensional models ; Tissue Engineering</subject><ispartof>PloS one, 2016-01, Vol.11 (1), p.e0146697-e0146697</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Cashman 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>2016 Cashman et al 2016 Cashman et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-c69f1111caa29fd98546226cb29bf447cc94f1e871aaf7e18b56c2573f2ed3203</citedby><cites>FETCH-LOGICAL-c758t-c69f1111caa29fd98546226cb29bf447cc94f1e871aaf7e18b56c2573f2ed3203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1758147328/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1758147328?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,730,783,787,888,25765,27936,27937,37024,37025,44602,53804,53806,75460</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26784941$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lionetti, Vincenzo</contributor><creatorcontrib>Cashman, Timothy J</creatorcontrib><creatorcontrib>Josowitz, Rebecca</creatorcontrib><creatorcontrib>Johnson, Bryce V</creatorcontrib><creatorcontrib>Gelb, Bruce D</creatorcontrib><creatorcontrib>Costa, Kevin D</creatorcontrib><title>Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new in vitro model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease.</description><subject>Aberration</subject><subject>Atrial Natriuretic Factor - genetics</subject><subject>Atrial Natriuretic Factor - metabolism</subject><subject>Atrial natriuretic peptide</subject><subject>Biomedical materials</subject><subject>Cardiac arrhythmia</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Cardiomyopathy, Hypertrophic - genetics</subject><subject>Cardiomyopathy, Hypertrophic - physiopathology</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Childrens health</subject><subject>Chlorofluorocarbons</subject><subject>Contraction</subject><subject>Coronary artery disease</subject><subject>Development and progression</subject><subject>Equipment and supplies</subject><subject>Gene expression</subject><subject>Genetic disorders</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Human subjects</subject><subject>Humans</subject><subject>Hypertrophic cardiomyopathy</subject><subject>Induced Pluripotent Stem Cells - cytology</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Kinases</subject><subject>MAP kinase</subject><subject>Medicine</subject><subject>Methods</subject><subject>Mutation</subject><subject>Myocardial Contraction</subject><subject>Myocytes</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - physiology</subject><subject>Patients</subject><subject>Pluripotency</subject><subject>Principal components analysis</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Rodents</subject><subject>Signaling</subject><subject>Stem cells</subject><subject>Stiffness</subject><subject>Substrates</subject><subject>Three dimensional models</subject><subject>Tissue Engineering</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYmPwDxBEQkJw0RJ_5MM3SCVaaaWhoW7j1nKd49RTEgfbmeh_4cfi0mxq0S5ILpKcPOc99utzoug1SqaI5OjTrRlsJ5ppbzqYJohmGcufRKeIETzJcEKeHryfRC-cu02SlBRZ9jw6wVleUEbRafR7MbSii8-7WncAFqq4FLbSQsbX2rkBXFxaED7Eb5zu6njZVYMMX9-bwereeOh8fOWhjUtoGhev4A5EE8-HTnptwvLiciOskB6sdl5LFxsVf1nN5pNvEKrsdBfbHqy3pt9ouS9u2q3phd9sX0bPlGgcvBqfZ9HN_Py6XEwuLr8uy9nFROZp4ScyYwqFSwqBmapYkdIM40yuMVsrSnMpGVUIihwJoXJAxTrNJE5zojBUJNhzFr3d6_aNcXw01nEU1BHNCS4CsdwTlRG3vLe6FXbLjdD8b8DYmgsb9tcAJ4kgCknEaEIpTquiAspIDowCKJGioPV5rDasW6hksNCK5kj0-E-nN7w2d5zmqEgJCQIfRgFrfoYj8rzVTgb_RQdm2K07S4q8KFga0Hf_oI_vbqRqETagO2VCXbkT5TNKk5RhRHGgpo9Q4a6g1TJ0odIhfpTw8SghMB5--VoMzvHl1er_2csfx-z7A3YTGs5vnGmGXce5Y5DuQWmNcxbUg8ko4bshuneD74aIj0MU0t4cHtBD0v3UkD8evhj8</recordid><startdate>20160119</startdate><enddate>20160119</enddate><creator>Cashman, Timothy J</creator><creator>Josowitz, Rebecca</creator><creator>Johnson, Bryce V</creator><creator>Gelb, Bruce D</creator><creator>Costa, Kevin D</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20160119</creationdate><title>Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy</title><author>Cashman, Timothy J ; Josowitz, Rebecca ; Johnson, Bryce V ; Gelb, Bruce D ; Costa, Kevin D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-c69f1111caa29fd98546226cb29bf447cc94f1e871aaf7e18b56c2573f2ed3203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aberration</topic><topic>Atrial Natriuretic Factor - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cashman, Timothy J</au><au>Josowitz, Rebecca</au><au>Johnson, Bryce V</au><au>Gelb, Bruce D</au><au>Costa, Kevin D</au><au>Lionetti, Vincenzo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-01-19</date><risdate>2016</risdate><volume>11</volume><issue>1</issue><spage>e0146697</spage><epage>e0146697</epage><pages>e0146697-e0146697</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new in vitro model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26784941</pmid><doi>10.1371/journal.pone.0146697</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2016-01, Vol.11 (1), p.e0146697-e0146697 |
| issn | 1932-6203 1932-6203 |
| language | eng |
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| source | Publicly Available Content Database; PubMed Central |
| subjects | Aberration Atrial Natriuretic Factor - genetics Atrial Natriuretic Factor - metabolism Atrial natriuretic peptide Biomedical materials Cardiac arrhythmia Cardiomyocytes Cardiomyopathy Cardiomyopathy, Hypertrophic - genetics Cardiomyopathy, Hypertrophic - physiopathology Cell culture Cell cycle Cell Differentiation Cells, Cultured Childrens health Chlorofluorocarbons Contraction Coronary artery disease Development and progression Equipment and supplies Gene expression Genetic disorders Health aspects Heart Heart diseases Human subjects Humans Hypertrophic cardiomyopathy Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Kinases MAP kinase Medicine Methods Mutation Myocardial Contraction Myocytes Myocytes, Cardiac - cytology Myocytes, Cardiac - metabolism Myocytes, Cardiac - physiology Patients Pluripotency Principal components analysis Proto-Oncogene Proteins B-raf - genetics Rodents Signaling Stem cells Stiffness Substrates Three dimensional models Tissue Engineering |
| title | Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-11-13T08%3A13%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Human%20Engineered%20Cardiac%20Tissues%20Created%20Using%20Induced%20Pluripotent%20Stem%20Cells%20Reveal%20Functional%20Characteristics%20of%20BRAF-Mediated%20Hypertrophic%20Cardiomyopathy&rft.jtitle=PloS%20one&rft.au=Cashman,%20Timothy%20J&rft.date=2016-01-19&rft.volume=11&rft.issue=1&rft.spage=e0146697&rft.epage=e0146697&rft.pages=e0146697-e0146697&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0146697&rft_dat=%3Cgale_plos_%3EA440592142%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c758t-c69f1111caa29fd98546226cb29bf447cc94f1e871aaf7e18b56c2573f2ed3203%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1758147328&rft_id=info:pmid/26784941&rft_galeid=A440592142&rfr_iscdi=true |