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

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.

mRNA – A game changer in regenerative medicine, cell-based therapy and reprogramming strategies

“…Another attempt in 2019 found that MSCs derived from adipose tissue can partly be directed towards the cardiac lineage using mod-mRNAs for Gata4, Mef2C, Tbx5 and Mesp1, while cells isolated from bone marrow, and dental follicle demonstrated only weak reprogramming efficiency [238] . Although full maturity of cardiomyocytes could not be reached in the study, the data suggest that adult MSCs can acquire a cardiac-like phenotype and might serve as source for cell replacement strategies in heart regeneration.…”

mRNA-Enhanced Cell Therapy and Cardiovascular Regeneration

“…Although optimization of mRNA constructs and delivery vehicles are still necessary to introduce such therapies into the clinical practice, they hold great promise as proof-of-concept studies emerge. For instance, cardiac reprogramming of human mesenchymal stromal cells with an mRNA differentiation cocktail has been demonstrated recently [ 38 ]. Similarly, overexpression of human vascular endothelial growth factor A ( VEGFA ) with mRNA promotes endothelial specification of the human ISL1 + progenitors as well as their engraftment, proliferation and survival in vivo [ 39 ].…”

A preview of selected articles

“…Recent studies have sought to improve the treatment of ischemic heart failure with patient‐derived MSCs by optimizing cardioreparative capacity through co‐instruction with specific cocktails of growth factors; however, this approach remains expensive due to the need for recombinant proteins and represents a significant challenge to scale. This vexing problem prompted researchers led by Atta Behfar (Mayo Clinic, Rochester, Minnesota, USA) to explore an alternative strategy ‐ the induction of enhanced cardiopoiesis (the production of cardiac muscle tissue) by MSCs through targeted gene delivery employing microencapsulated‐modified‐messenger RNA technology 15,16 . In their recent STEM CELLS article, Li et al 11 employed a screening of known mesodermal and pre‐cardiac transcription factors to highlight brachyury expression as a potentially exciting means of engineering a cardiopoietic phenotype in adipose‐derived MSCs.…”