Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction
Abstract Aims Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are...
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Veröffentlicht in: | Cardiovascular research 2020-03, Vol.116 (3), p.545-553 |
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description | Abstract
Aims
Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner.
Methods and results
CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered.
Conclusion
Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs.
Graphical Abstract
Graphical Abstract |
doi_str_mv | 10.1093/cvr/cvz181 |
format | Article |
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Aims
Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner.
Methods and results
CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered.
Conclusion
Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvz181</identifier><identifier>PMID: 31287499</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Fast-Track Original</subject><ispartof>Cardiovascular research, 2020-03, Vol.116 (3), p.545-553</ispartof><rights>The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology 2019</rights><rights>The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-e78256ee5bfc3370ae2ded8c62a5d05514d66d190775bd09b98c5e9a16ca062f3</citedby><cites>FETCH-LOGICAL-c408t-e78256ee5bfc3370ae2ded8c62a5d05514d66d190775bd09b98c5e9a16ca062f3</cites><orcidid>0000-0002-9956-7116 ; 0000-0003-1831-7412 ; 0000-0002-3466-5401 ; 0000-0002-5985-6626</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31287499$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schwach, Verena</creatorcontrib><creatorcontrib>Gomes Fernandes, Maria</creatorcontrib><creatorcontrib>Maas, Saskia</creatorcontrib><creatorcontrib>Gerhardt, Sophie</creatorcontrib><creatorcontrib>Tsonaka, Roula</creatorcontrib><creatorcontrib>van der Weerd, Louise</creatorcontrib><creatorcontrib>Passier, Robert</creatorcontrib><creatorcontrib>Mummery, Christine L</creatorcontrib><creatorcontrib>Birket, Matthew J</creatorcontrib><creatorcontrib>Salvatori, Daniela C F</creatorcontrib><title>Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Abstract
Aims
Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner.
Methods and results
CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered.
Conclusion
Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs.
Graphical Abstract
Graphical Abstract</description><subject>Fast-Track Original</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><recordid>eNp9kU1rFTEUhoMo9lrd-AMkG0EKo0lmksxshFLqBxTc6DqcSc7cRmaSMclcWn-9qbcW3bgI4XAenuTlJeQlZ285G9p39pDq-cl7_ojsuJayaUUnH5MdY6xvVKvaE_Is5-91lFJ3T8lJy0Wvu2HYkXJ5s0JwMM5Ir7cFArWQnI8HyHabIdE1xT0GX2LKdEpxobngQi3Oc51jognrGhMUH_Z0iVuuHoRUKEwFE11u428hzNSHCZItPobn5MkEc8YX9_cp-fbh8uvFp-bqy8fPF-dXje1YXxrUvZAKUY6TbVvNAIVD11slQLoahXdOKccHprUcHRvGobcSB-DKAlNiak_J-6N33cYFncVQEsxmTX6BdGsiePPvJvhrs48Ho4UUXceq4M29IMUfG-ZiFp_vskPAGtUIITvJtdJDRc-OqE0x54TTwzOcmbuaTK3JHGuq8Ku_P_aA_umlAq-PQNzW_4l-AZ6loFs</recordid><startdate>20200301</startdate><enddate>20200301</enddate><creator>Schwach, Verena</creator><creator>Gomes Fernandes, Maria</creator><creator>Maas, Saskia</creator><creator>Gerhardt, Sophie</creator><creator>Tsonaka, Roula</creator><creator>van der Weerd, Louise</creator><creator>Passier, Robert</creator><creator>Mummery, Christine L</creator><creator>Birket, Matthew J</creator><creator>Salvatori, Daniela C F</creator><general>Oxford University Press</general><scope>TOX</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9956-7116</orcidid><orcidid>https://orcid.org/0000-0003-1831-7412</orcidid><orcidid>https://orcid.org/0000-0002-3466-5401</orcidid><orcidid>https://orcid.org/0000-0002-5985-6626</orcidid></search><sort><creationdate>20200301</creationdate><title>Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction</title><author>Schwach, Verena ; Gomes Fernandes, Maria ; Maas, Saskia ; Gerhardt, Sophie ; Tsonaka, Roula ; van der Weerd, Louise ; Passier, Robert ; Mummery, Christine L ; Birket, Matthew J ; Salvatori, Daniela C F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-e78256ee5bfc3370ae2ded8c62a5d05514d66d190775bd09b98c5e9a16ca062f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Fast-Track Original</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schwach, Verena</creatorcontrib><creatorcontrib>Gomes Fernandes, Maria</creatorcontrib><creatorcontrib>Maas, Saskia</creatorcontrib><creatorcontrib>Gerhardt, Sophie</creatorcontrib><creatorcontrib>Tsonaka, Roula</creatorcontrib><creatorcontrib>van der Weerd, Louise</creatorcontrib><creatorcontrib>Passier, Robert</creatorcontrib><creatorcontrib>Mummery, Christine L</creatorcontrib><creatorcontrib>Birket, Matthew J</creatorcontrib><creatorcontrib>Salvatori, Daniela C F</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schwach, Verena</au><au>Gomes Fernandes, Maria</au><au>Maas, Saskia</au><au>Gerhardt, Sophie</au><au>Tsonaka, Roula</au><au>van der Weerd, Louise</au><au>Passier, Robert</au><au>Mummery, Christine L</au><au>Birket, Matthew J</au><au>Salvatori, Daniela C F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>116</volume><issue>3</issue><spage>545</spage><epage>553</epage><pages>545-553</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><abstract>Abstract
Aims
Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner.
Methods and results
CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered.
Conclusion
Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs.
Graphical Abstract
Graphical Abstract</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>31287499</pmid><doi>10.1093/cvr/cvz181</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-9956-7116</orcidid><orcidid>https://orcid.org/0000-0003-1831-7412</orcidid><orcidid>https://orcid.org/0000-0002-3466-5401</orcidid><orcidid>https://orcid.org/0000-0002-5985-6626</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Fast-Track Original |
title | Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction |
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