Publication Date:
2009-07-07
Description:
MicroRNAs (miRNAs) are regulators of myriad cellular events, but evidence for a single miRNA that can efficiently differentiate multipotent stem cells into a specific lineage or regulate direct reprogramming of cells into an alternative cell fate has been elusive. Here we show that miR-145 and miR-143 are co-transcribed in multipotent murine cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem-cell-derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2-5 (NK2 transcription factor related, locus 5) and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4 (Kruppel-like factor 4), myocardin and Elk-1 (ELK1, member of ETS oncogene family), to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769203/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769203/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cordes, Kimberly R -- Sheehy, Neil T -- White, Mark P -- Berry, Emily C -- Morton, Sarah U -- Muth, Alecia N -- Lee, Ting-Hein -- Miano, Joseph M -- Ivey, Kathryn N -- Srivastava, Deepak -- C06 RR018928/RR/NCRR NIH HHS/ -- HL091168/HL/NHLBI NIH HHS/ -- HL62572/HL/NHLBI NIH HHS/ -- R01 HL062572/HL/NHLBI NIH HHS/ -- R01 HL062572-12/HL/NHLBI NIH HHS/ -- R01 HL091168/HL/NHLBI NIH HHS/ -- R01 HL091168-01A1/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Aug 6;460(7256):705-10. doi: 10.1038/nature08195. Epub 2009 Jul 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19578358" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Differentiation
;
*Cell Lineage
;
Cell Proliferation
;
Female
;
Gene Expression Regulation
;
Homeodomain Proteins/metabolism
;
Male
;
Mice
;
Mice, Transgenic
;
MicroRNAs/genetics/*metabolism
;
Models, Biological
;
Myocardium/metabolism
;
Myocytes, Smooth Muscle/*cytology/*metabolism
;
Transcription Factors/metabolism
;
Transcription, Genetic
;
Vascular Diseases/metabolism
;
ets-Domain Protein Elk-4/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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