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

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.

• Authors: Lior Zangi, Kathy O Lui, Alexander von Gise, Qing Ma, Wataru Ebina, Leon M Ptaszek, Daniela Später, Huansheng Xu, Mohammadsharif Tabebordbar, Rostic Gorbatov, Brena Sena, Matthias Nahrendorf, David M Briscoe, Ronald A Li, Amy J Wagers, Derrick J Rossi, William T Pu, Kenneth R Chien
• Journal: Nature biotechnology (Nat Biotechnol) Vol. 31 Issue 10 Pg. 898-907 (Oct 2013) ISSN: 1546-1696 [Electronic] United States
• PMID: 24013197 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Luciferases
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Apoptosis
• Biomarkers (metabolism)
• Cell Differentiation
• Cell Lineage
• Cell Proliferation
• Disease Models, Animal
• Endothelial Cells (pathology)
• Gene Transfer Techniques
• Humans
• Kinetics
• Luciferases (metabolism)
• Mice
• Models, Biological
• Muscle, Skeletal (metabolism)
• Myocardial Infarction (physiopathology, therapy)
• Myocardium (metabolism, pathology)
• RNA, Messenger (genetics, metabolism)
• Regeneration
• Stem Cell Transplantation
• Stem Cells (cytology, metabolism)
• Survival Analysis
• Treatment Outcome
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)