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

By L. Zangi, Kathy O. Lui, A. von Gise, Q. Ma, Wataru Ebina, L. Ptaszek, Daniela Später, Huansheng Xu, Mohammadsharif Tabebordbar, Rostic Gorbatov and 8 more. Nature Biotechnology, 2013

628 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/81fe48dd599dd37a027595691594f617137d1365

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In Molecular Biology

1. Daniel G. Anderson
2. Piotr S. Kowalski
3. Arnab Rudra
4. Lei Miao
5. Ugur Sahin
6. Ö. Türeci
7. K. Karikó

Citations in the corpus

• Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. (2019, positive): “Intramyocardial injection of modified RNA encoding human VEGF-A, complexed with RNAiMAX, has been reported to improve heart function and long-term survival of mice with myocardial infarction.(101) Turnbull et al.”
• mRNA-based therapeutics — developing a new class of drugs (2014, positive): “It was also demonstrated that direct intramyocardial injection of IVT mRNA containing pseudouridine and 5-methylcytidine, and encoding vascular endothelial growth factor A (VEGFA), improved heart function and enhanced long-term survival in a mouse model of myocardial infarction 23 .”