cells Review mRNA-Enhanced Cell Therapy and Cardiovascular Regeneration Palas K. Chanda , Roman Sukhovershin and John P. Cooke *   Citation: Chanda, P.K.; Sukhovershin, R.; Cooke, J.P. mRNA-Enhanced Cell Therapy and Cardiovascular Regeneration. Cells 2021, 10, 187. https://doi.org/ 10.3390/cells10010187 Received: 4 December 2020 Accepted: 16 January 2021 Published: 19 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). RNA Therapeutics Program, Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; pkchanda@houstonmethodist.org (P.K.C.); rsukhovershin@houstonmethodist.org (R.S.) * Correspondence: jpcooke@houstonmethodist.org; Tel.: +1-713-441-6885 Abstract: mRNA has emerged as an important biomolecule in the global call for the development of therapies during the COVID-19 pandemic. Synthetic in vitro-transcribed (IVT) mRNA can be engineered to mimic naturally occurring mRNA and can be used as a tool to target “undruggable” diseases. Recent advancement in the field of RNA therapeutics have addressed the challenges inherent to this drug molecule and this approach is now being applied to several therapeutic modalities, from cancer immunotherapy to vaccine development. In this review, we discussed the use of mRNA for stem cell generation or enhancement for the purpose of cardiovascular regeneration. Keywords: RNA therapeutics; cell therapy; cardiovascular regeneration; inflammatory signaling; nuclear reprogramming; iPSCs; transdifferentiation; cardiovascular ageing 1. Introduction Advances in the biopharmaceutical industry were accelerated in the global race toward therapies for the COVID-19 pandemic [1]. Most notably, messenger ribonucleic acid (mRNA) vaccines galvanized the field, with lightspeed generation of new therapeutic molecules. For example, within 42 days of the publication of the SARS-CoV-2 sequence by Chinese scientists in January 2020 [2], Moderna sent its RNA vaccine candidate to the National Institute of Allergy and Infectious Disease for preclinical testing. By April 2020, Moderna launched its first clinical trial. Less than 8 months later, Moderna will be seeking Emergency Use Authorization for its vaccine, after phase III trials revealed 95% efficacy and excellent safety. Out of the 236 COVID-19 vaccines being developed, 29 of them are mRNA-based [1] and the first two (BNT162 from Pfizer and MRNA1273 from Moderna) of all the vaccines to complete the phase III clinical trial belong to this category [3,4]. These vaccines will be the first mRNA therapeutics to reach the market. The speed by which mRNA vaccines were developed, and their high degree of efficacy and safety, has brought attention to the great promise of mRNA therapeutics. Whereas the majority of drugs approved by U.S. Food and Drug Administration (FDA) are small molecules, such drugs have limitations in the range of diseases that are “druggable” [5,6]. In contrast, mRNA has nearly limitless range, as this biological software can be rapidly modified to encode any therapeutic protein or antigen of interest. Furthermore, with advances in delivery methods, pharmacokinetic and pharmacodynamic properties, enhanced efficacy and stability and reduced immunogenicity and production costs [7,8], mRNA therapeutics have an almost limitless potential. mRNA therapeutics offers several advantages over the contemporary small molecule, protein or DNA-based therapies. For example, it is difficult to generate small molecules that will allosterically enhance the activity of a deficient enzyme. It may also be difficult to generate a properly folded and post-translationally modified recombinant protein for the same deficit. By contrast, mRNA encoding the wild-type enzyme is easily generated, and when delivered to the appropriate cell type, can replace the deficient enzyme. Compared to Cells 2021, 10, 187. https://doi.org/10.3390/cells10010187 https://www.mdpi.com/journal/cells