Concise Review: Application of Chemically Modified mRNA in Cell Fate Conversion and Tissue Engineering

Abstract

Chemically modified RNA (cmRNA) has potential as a safe and efficient tool for nucleic acid-based therapies and regenerative medicine. Modifications in the chemistry of mRNA can enhance stability, reduce immunogenicity, and thus facilitate mRNA-based nucleic acid therapy, which eliminates risk of insertional mutagenesis. In addition to these valuable advantages, the mRNA-based method showed significantly higher efficacy for reprogramming somatic cells to pluripotency compared with DNA- or protein-based methods. These findings suggest cmRNA can provide a powerful and safe tool for cell programming and reprogramming. Delivery methods, particularly using lipid nanoparticles, provide strategies for cell and organ-specific targeting. The present study comprehensively compares studies that have used cmRNAs for cell fate conversion and tissue engineering. The information should be useful for investigators looking to choose the most efficient and straightforward cmRNA-based strategy and protocol for tissue engineering and regenerative medicine research. Stem Cells Translational Medicine 2019;8:833&843.

Keywords: Cell programming and reprogramming; Differentiation; Nanoparticles; Nucleic acid therapy; Regenerative medicine; iPSCs.

Figure 1

General structure of chemically modified mRNA (cmRNA). Modifications increase the stability, decrease the immunogenicity, and in some cases increase the translational efficiency. Typical components of a cmRNA include, with color‐coding: 7‐methylguanosine (m7G) cap structure (5′‐Cap). Untranslated regions (5′‐UTR and 3′‐UTR), usually derived from β‐globin mRNAs. Open reading frame, coding sequence for the gene of interest, containing optimized codons and/or chemically modified nucleotides. Polyadenylated tail (Poly[A] tail), stretch of 100–200 adenine nucleotides.

Figure 2

Application of mRNAs in cell and tissue engineering. mRNA can be used for reprogramming (dedifferentiation) of somatic cells to stem cells or directed differentiation of stem cells to the desired cell type. In addition, somatic cells can be directly reprogrammed to a distinct somatic cell type (trans‐differentiation) using mRNAs. Direct injection of therapeutic mRNAs to defective organs (in situ mRNA delivery) may also trigger tissue regeneration. This figure was made in part by using the Servier medical art free image collection.

Figure 3

Noninvasive and targeted delivery of chemically modified mRNAs (cmRNAs) in vivo. Negatively charged cmRNA molecules bind electrostatically with positively charged polymers or lipids. Various strategies have been used to target the resulting nanoparticles to certain tissues. Systemic (blood), inhaled, or local injections have been used to preferentially target liver hepatocytes, lung epithelium, or skeletal muscle, respectively. Decorating the nanoparticles with monoclonal antibodies has been used to target leukocytes expressing defined antigens, whereas defined lipid/polymer formulations can bias delivery to distinct cells and tissues, including endothelium. See text for details and relevant references. This figure was made in part by using the Servier medical art free image collection and the library of Science & Medical Illustrations.