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Nat Biotechnol. 2013 Oct;31(10):898-907. doi: 10.1038/nbt.2682. Epub 2013 Sep 8.

Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction.

Author information

1
1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts, USA. [4] Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts, USA. [5] Boston and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [6].

Abstract

In a cell-free approach to regenerative therapeutics, transient application of paracrine factors in vivo could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) results in the expansion and directed differentiation of endogenous heart progenitors in a mouse myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct in vivo comparison with DNA vectors and temporal control with VEGF inhibitors revealed the greatly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long-term organ repair.

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PMID:
24013197
PMCID:
PMC4058317
DOI:
10.1038/nbt.2682
[Indexed for MEDLINE]
Free PMC Article

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