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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This work was funded by US National Institutes of Health U01H100408 (K.R.C.), U01HL098166 (K.R.C.), U01JL100401 (W.T.P.), R01HL094683 (W.T.P.), RC1HL099618 (K.R.C., W.T.P.) and UO1HL100402 (A.J.W.). K.O.L. held a Croucher Foundation Fellowship and A.J.W. is an Early Career Scientist of the Howard Hughes Medical Institute. We thank R. Liao, J. Guan, J. Truelove, L. Bu, M. Stachel, K. Buac, V. Priestly, R. Gazit, K. Ketman, N. Barteneva, A. He, S. Stevens, B. Zhou and L.Warren for all their help in this project. Adult cardiomyocytes were a kind gift from R. Liao (Biological and Biomaterial Science, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School).
K.R.C. and D.J.R. are co-founders of Moderna Therapeutics, a Cambridge, Massachusetts company that is developing therapeutics based on modified mRNA. K.R.C. is an advisor to AstraZeneca, which has an interest in cardiovascular therapeutic applications of modRNA.
Supplemental Appendix, Supplementary Tables 1-6, and Supplementary Figures 1-12 (PDF 24781 kb)
Cine MRI of sham-operated heart, 21 days after operation (MOV 915 kb)
Cine MRI of MI heart, vehicle treated heart, 21 days after operation (MOV 836 kb)
Cine MRI of MI heart, VEGF-A modRNA treated, 21 days after operation (MOV 871 kb)
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Zangi, L., Lui, K., von Gise, A. et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 31, 898–907 (2013). https://doi.org/10.1038/nbt.2682
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