| MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. | |
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MedLine Citation:
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PMID: 22539765 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas to functional tissue in situ. OBJECTIVE: The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo. METHODS AND RESULTS: Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin. CONCLUSIONS: The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general. |
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Authors:
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Tilanthi M Jayawardena; Bakytbek Egemnazarov; Elizabeth A Finch; Lunan Zhang; J Alan Payne; Kumar Pandya; Zhiping Zhang; Paul Rosenberg; Maria Mirotsou; Victor J Dzau |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-04-26 |
Journal Detail:
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Title: Circulation research Volume: 110 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-25 Completed Date: 2012-07-30 Revised Date: 2013-05-28 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1465-73 Citation Subset: IM |
Affiliation:
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Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC 27710, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Transdifferentiation* / drug effects, genetics Cells, Cultured Disease Models, Animal Fibroblasts / drug effects, metabolism*, pathology Gene Expression Regulation Genetic Therapy / methods Janus Kinase 1 / antagonists & inhibitors, metabolism Luminescent Proteins / genetics, metabolism Male Mice Mice, Inbred C57BL Mice, Transgenic MicroRNAs / administration & dosage, metabolism* Myocardial Contraction Myocardial Ischemia / genetics, metabolism, pathology, physiopathology, therapy Myocytes, Cardiac / drug effects, metabolism*, pathology Protein Kinase Inhibitors / pharmacology Recovery of Function Regeneration S100 Proteins / genetics, metabolism Transfection |
| Grant Support | |
ID/Acronym/Agency:
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HL49277/HL/NHLBI NIH HHS; HL72010/HL/NHLBI NIH HHS; HL73219/HL/NHLBI NIH HHS; HL81744/HL/NHLBI NIH HHS; R01 HL035610/HL/NHLBI NIH HHS; R01 HL049277/HL/NHLBI NIH HHS; R01 HL072010/HL/NHLBI NIH HHS; R01 HL081744/HL/NHLBI NIH HHS; R01 HL093470/HL/NHLBI NIH HHS; R01 HL35610/HL/NHLBI NIH HHS; R01-HL093470/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Jak1 protein, mouse; 0/Luminescent Proteins; 0/MicroRNAs; 0/Protein Kinase Inhibitors; 0/S100 Proteins; 0/red fluorescent protein; EC 2.7.10.2/Janus Kinase 1 |
| Comments/Corrections | |
Comment In:
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Circ Res. 2012 May 25;110(11):1392-4
[PMID:
22628569
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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