Document Detail


MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.
MedLine Citation:
PMID:  22539765     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tilanthi M Jayawardena; Bakytbek Egemnazarov; Elizabeth A Finch; Lunan Zhang; J Alan Payne; Kumar Pandya; Zhiping Zhang; Paul Rosenberg; Maria Mirotsou; Victor J Dzau
Related Documents :
14207055 - Invasion and destruction of homologous kidney by locally inoculated lymphoid cells.
2852075 - Cell and molecular studies of renin secretion.
2986155 - Complement-mediated arachidonate metabolism.
6263715 - Possible link between converting enzyme inhibition and renomedullary interstitial cells.
10813365 - Glutathione-dependent cytotoxicity of the chloroacetanilide herbicides alachlor, metola...
24375635 - The spectral karyotype of l5178y tk(+/-) mouse lymphoma cells clone 3.7.2c and factors ...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-26
Journal Detail:
Title:  Circulation research     Volume:  110     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-25     Completed Date:  2012-07-30     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1465-73     Citation Subset:  IM    
Affiliation:
Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC 27710, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
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:
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:
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:
Circ Res. 2012 May 25;110(11):1392-4   [PMID:  22628569 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Effects of aging on angiogenesis.
Next Document:  Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia.