**RNA-Based Strategies for Cardiac Reprogramming of Human Mesenchymal Stromal Cells**

**Paula Mueller 1,2, Markus Wolfien 3, Katharina Ekat 4, Cajetan Immanuel Lang 5, Dirk Koczan 6, Olaf Wolkenhauer 3,7, Olga Hahn 4, Kirsten Peters 4, Hermann Lang 8, Robert David 1,2,\* and Heiko Lemcke 1,2**


Received: 6 December 2019; Accepted: 17 February 2020; Published: 22 February 2020

**Abstract:** Multipotent adult mesenchymal stromal cells (MSCs) could represent an elegant source for the generation of patient-specific cardiomyocytes needed for regenerative medicine, cardiovascular research, and pharmacological studies. However, the differentiation of adult MSC into a cardiac lineage is challenging compared to embryonic stem cells or induced pluripotent stem cells. Here we used non-integrative methods, including microRNA and mRNA, for cardiac reprogramming of adult MSC derived from bone marrow, dental follicle, and adipose tissue. We found that MSC derived from adipose tissue can partly be reprogrammed into the cardiac lineage by transient overexpression of GATA4, TBX5, MEF2C, and MESP1, while cells isolated from bone marrow, and dental follicle exhibit only weak reprogramming efficiency. qRT-PCR and transcriptomic analysis revealed activation of a cardiac-specific gene program and up-regulation of genes known to promote cardiac development. Although we did not observe the formation of fully mature cardiomyocytes, our data suggests that adult MSC have the capability to acquire a cardiac-like phenotype when treated with mRNA coding for transcription factors that regulate heart development. Yet, further optimization of the reprogramming process is mandatory to increase the reprogramming efficiency.

**Keywords:** mesenchymal stromal cells (MSC); mRNA; miRNA; cardiac reprogramming; cardiac differentiation
