Abstract
Ischemic heart disease is the major cause of mortality worldwide. Despite the most recent pharmacological progresses, cardiac regeneration is yet not possible, and heart transplantation is the only therapeutic option for end-stage heart failure. Traditional cardiac regenerative medicine approaches, such as cell therapies and tissue engineering, have failed in the obtainment of human functional cardiac tissue, mainly due to unavailability of high quantities of autologous functional cardiomyocytes (CMs), low grafting efficiency, and/or arrhythmic events. Direct reprogramming (DR) of fibroblasts into induced CMs (iCMs) has emerged as a new promising approach for myocardial regeneration by in situ transdifferentiation or providing additional CM source for cell therapy. Among available DR methods, non-viral transfection with microRNAs (miRcombo: miR-1, miR-133, miR-208, and miR-499) appears promising for future clinical translation. MiRcombo transfection of fibroblasts could be significantly improved by the development of safe nanocarriers, efficiently delivering their cargo to target cells at the required stoichiometric ratio and overall dose in due times. Newly designed in vitro 3D culture microenvironments, providing biomimetic biophysical and biochemical stimuli to miRcombo-transfected cells, significantly increase the yield of fibroblast transdifferentiation into iCMs, enhancing CM gene expression. Epigenetic regulation of gene expression programs, critical to cell lineage commitment, can also be promoted by the administration of specific anti-inflammatory and anti-fibrotic soluble factors, helping in suppressing fibroblast signature. The aim of this mini-review is to introduce the readers to a relatively unknown field of cardiac research integrating bioengineering tools as relevant for the progress of miRNA-mediated cardiac DR.
Highlights
Ischemic heart disease is a major cause of mortality with more than 23 million cases worldwide [1, 2]
Main limitations include the low yield of fibroblast Direct reprogramming (DR) into induced CMs (iCMs), the wide use of unsafe viral vectors, and the generation of predominantly immature, partially reprogrammed iCMs [11, 12]
Zhao et al have reported that DR is enhanced in GHMTtransfected mouse fibroblasts by overexpressing miR-1 and miR133 combined with rho-associated kinase (ROCK) or TGF-β inhibitors, suggesting a synergistic effect in overcoming reprogramming barriers [16]
Summary
Ischemic heart disease is a major cause of mortality with more than 23 million cases worldwide [1, 2]. During myocardial infarction (MI), billions of cardiomyocytes (CMs) are irreversibly lost and replaced by cardiac fibroblasts (CFs) forming a non-contractile scar tissue, which undergoes continuous remodeling, causing left ventricle dilation and progressive heart failure [3, 4]. Given the poor endogenous regenerative potential of the adult heart, recovery of cardiac functionality could be accomplished by the replenishment of lost CMs. cell therapies and cardiac
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