Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart
Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differ...
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| Veröffentlicht in: | The Journal of clinical investigation 2018-05, Vol.128 (5), p.2127-2143 |
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| creator | Fu, Xing Khalil, Hadi Kanisicak, Onur Boyer, Justin G Vagnozzi, Ronald J Maliken, Bryan D Sargent, Michelle A Prasad, Vikram Valiente-Alandi, Iñigo Blaxall, Burns C Molkentin, Jeffery D |
| description | Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar. |
| doi_str_mv | 10.1172/JCI98215 |
| format | Article |
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With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.</description><identifier>ISSN: 0021-9738</identifier><identifier>ISSN: 1558-8238</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI98215</identifier><identifier>PMID: 29664017</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Actin ; Animal models ; Animals ; Apoptosis ; Biomedical research ; Cardiomyocytes ; Cell Differentiation ; Cicatrices ; Cicatrix - metabolism ; Cicatrix - pathology ; Collagen ; Complications and side effects ; Cytological research ; Development and progression ; Extracellular matrix ; Extracellular Matrix - metabolism ; Extracellular Matrix - pathology ; Extracellular Matrix Proteins - metabolism ; Female ; Fibroblasts ; Genes ; Genetic engineering ; Growth factors ; Health aspects ; Heart attack ; Heart attacks ; Humans ; Kinases ; Male ; Medical research ; Mice ; Myoblasts, Cardiac - metabolism ; Myoblasts, Cardiac - pathology ; Myocardial infarction ; Myocardial Infarction - metabolism ; Myocardial Infarction - pathology ; Myocardium - metabolism ; Myocardium - pathology ; Myofibroblasts - metabolism ; Myofibroblasts - pathology ; Phenotypes ; Physiological aspects ; Proteins ; Rodents ; Scars ; Smooth muscle ; Wound healing</subject><ispartof>The Journal of clinical investigation, 2018-05, Vol.128 (5), p.2127-2143</ispartof><rights>COPYRIGHT 2018 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation May 2018</rights><rights>Copyright © 2018 Fu et al. 2018 Fu et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c709t-4d06d9934f1f87444bfbe0ab729af9691bc3d3bdda5bb26231a02a319b22ae903</citedby><cites>FETCH-LOGICAL-c709t-4d06d9934f1f87444bfbe0ab729af9691bc3d3bdda5bb26231a02a319b22ae903</cites><orcidid>0000-0002-8393-4874 ; 0000-0002-3558-6529</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957472/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957472/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29664017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fu, Xing</creatorcontrib><creatorcontrib>Khalil, Hadi</creatorcontrib><creatorcontrib>Kanisicak, Onur</creatorcontrib><creatorcontrib>Boyer, Justin G</creatorcontrib><creatorcontrib>Vagnozzi, Ronald J</creatorcontrib><creatorcontrib>Maliken, Bryan D</creatorcontrib><creatorcontrib>Sargent, Michelle A</creatorcontrib><creatorcontrib>Prasad, Vikram</creatorcontrib><creatorcontrib>Valiente-Alandi, Iñigo</creatorcontrib><creatorcontrib>Blaxall, Burns C</creatorcontrib><creatorcontrib>Molkentin, Jeffery D</creatorcontrib><title>Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.</description><subject>Actin</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biomedical research</subject><subject>Cardiomyocytes</subject><subject>Cell Differentiation</subject><subject>Cicatrices</subject><subject>Cicatrix - metabolism</subject><subject>Cicatrix - pathology</subject><subject>Collagen</subject><subject>Complications and side effects</subject><subject>Cytological research</subject><subject>Development and progression</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - metabolism</subject><subject>Extracellular Matrix - pathology</subject><subject>Extracellular Matrix Proteins - metabolism</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Genes</subject><subject>Genetic engineering</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>Heart attack</subject><subject>Heart attacks</subject><subject>Humans</subject><subject>Kinases</subject><subject>Male</subject><subject>Medical research</subject><subject>Mice</subject><subject>Myoblasts, Cardiac - metabolism</subject><subject>Myoblasts, Cardiac - pathology</subject><subject>Myocardial infarction</subject><subject>Myocardial Infarction - metabolism</subject><subject>Myocardial Infarction - pathology</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - pathology</subject><subject>Myofibroblasts - metabolism</subject><subject>Myofibroblasts - pathology</subject><subject>Phenotypes</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Scars</subject><subject>Smooth muscle</subject><subject>Wound healing</subject><issn>0021-9738</issn><issn>1558-8238</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkltrFDEUxwdR7FoFP4EMCKIPU3ObS16EsnhZKRSs-hpOMie7KTOTNcmI-unN4rZ2ZR8kDwdyfvnnXP5F8ZSSM0pb9vrjciU7Rut7xYLWdVd1jHf3iwUhjFay5d1J8SjGa0KoELV4WJww2TSC0HZRwNUWjYPB_cK-tE4HrweIqeydtRhwSg5SzsSUQyznqccwOCyjgVBaH0ZIzk-lm8q0wRwsBLPjRz9HLDcIIT0uHlgYIj7Zx9Piy7u3n5cfqovL96vl-UVlWiJTJXrS9FJyYantWiGEthoJ6JZJsLKRVBvec933UGvNGsYpEAacSs0YoCT8tHjzR3c76xF7k2sPMKhtcCOEn8qDU4eZyW3U2n9Xtaxb0bIs8HIvEPy3GWNSo4sGhwEmzO0oRlgjqKSUZvT5P-i1n8OU28tU3XR50Kz9S61hQJWH4_O_ZieqzmsuG9Hk_WSqOkKtccJcpJ_Qunx9wJ8d4fPpcXTm6INXBw8yk_BHWsMco1pdffp_9vLrIfviDpt3PaRN9MO8c0Q8BPeDNcHHGNDeLoUStfOvuvFvRp_dXeIteGNY_hvAJ-eO</recordid><startdate>20180501</startdate><enddate>20180501</enddate><creator>Fu, Xing</creator><creator>Khalil, Hadi</creator><creator>Kanisicak, Onur</creator><creator>Boyer, Justin G</creator><creator>Vagnozzi, Ronald J</creator><creator>Maliken, Bryan D</creator><creator>Sargent, Michelle A</creator><creator>Prasad, Vikram</creator><creator>Valiente-Alandi, Iñigo</creator><creator>Blaxall, Burns C</creator><creator>Molkentin, Jeffery D</creator><general>American Society for Clinical Investigation</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>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8393-4874</orcidid><orcidid>https://orcid.org/0000-0002-3558-6529</orcidid></search><sort><creationdate>20180501</creationdate><title>Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart</title><author>Fu, Xing ; Khalil, Hadi ; Kanisicak, Onur ; Boyer, Justin G ; Vagnozzi, Ronald J ; Maliken, Bryan D ; Sargent, Michelle A ; Prasad, Vikram ; Valiente-Alandi, Iñigo ; Blaxall, Burns C ; Molkentin, Jeffery D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c709t-4d06d9934f1f87444bfbe0ab729af9691bc3d3bdda5bb26231a02a319b22ae903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Actin</topic><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biomedical research</topic><topic>Cardiomyocytes</topic><topic>Cell Differentiation</topic><topic>Cicatrices</topic><topic>Cicatrix - metabolism</topic><topic>Cicatrix - pathology</topic><topic>Collagen</topic><topic>Complications and side effects</topic><topic>Cytological research</topic><topic>Development and progression</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix - metabolism</topic><topic>Extracellular Matrix - pathology</topic><topic>Extracellular Matrix Proteins - metabolism</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Genes</topic><topic>Genetic engineering</topic><topic>Growth factors</topic><topic>Health aspects</topic><topic>Heart attack</topic><topic>Heart attacks</topic><topic>Humans</topic><topic>Kinases</topic><topic>Male</topic><topic>Medical research</topic><topic>Mice</topic><topic>Myoblasts, Cardiac - metabolism</topic><topic>Myoblasts, Cardiac - pathology</topic><topic>Myocardial infarction</topic><topic>Myocardial Infarction - metabolism</topic><topic>Myocardial Infarction - pathology</topic><topic>Myocardium - metabolism</topic><topic>Myocardium - pathology</topic><topic>Myofibroblasts - metabolism</topic><topic>Myofibroblasts - pathology</topic><topic>Phenotypes</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Scars</topic><topic>Smooth muscle</topic><topic>Wound healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fu, Xing</creatorcontrib><creatorcontrib>Khalil, Hadi</creatorcontrib><creatorcontrib>Kanisicak, Onur</creatorcontrib><creatorcontrib>Boyer, Justin G</creatorcontrib><creatorcontrib>Vagnozzi, Ronald J</creatorcontrib><creatorcontrib>Maliken, Bryan D</creatorcontrib><creatorcontrib>Sargent, Michelle A</creatorcontrib><creatorcontrib>Prasad, Vikram</creatorcontrib><creatorcontrib>Valiente-Alandi, Iñigo</creatorcontrib><creatorcontrib>Blaxall, Burns C</creatorcontrib><creatorcontrib>Molkentin, Jeffery D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fu, Xing</au><au>Khalil, Hadi</au><au>Kanisicak, Onur</au><au>Boyer, Justin G</au><au>Vagnozzi, Ronald J</au><au>Maliken, Bryan D</au><au>Sargent, Michelle A</au><au>Prasad, Vikram</au><au>Valiente-Alandi, Iñigo</au><au>Blaxall, Burns C</au><au>Molkentin, Jeffery D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2018-05-01</date><risdate>2018</risdate><volume>128</volume><issue>5</issue><spage>2127</spage><epage>2143</epage><pages>2127-2143</pages><issn>0021-9738</issn><issn>1558-8238</issn><eissn>1558-8238</eissn><abstract>Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>29664017</pmid><doi>10.1172/JCI98215</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-8393-4874</orcidid><orcidid>https://orcid.org/0000-0002-3558-6529</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Actin Animal models Animals Apoptosis Biomedical research Cardiomyocytes Cell Differentiation Cicatrices Cicatrix - metabolism Cicatrix - pathology Collagen Complications and side effects Cytological research Development and progression Extracellular matrix Extracellular Matrix - metabolism Extracellular Matrix - pathology Extracellular Matrix Proteins - metabolism Female Fibroblasts Genes Genetic engineering Growth factors Health aspects Heart attack Heart attacks Humans Kinases Male Medical research Mice Myoblasts, Cardiac - metabolism Myoblasts, Cardiac - pathology Myocardial infarction Myocardial Infarction - metabolism Myocardial Infarction - pathology Myocardium - metabolism Myocardium - pathology Myofibroblasts - metabolism Myofibroblasts - pathology Phenotypes Physiological aspects Proteins Rodents Scars Smooth muscle Wound healing |
| title | Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart |
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