Table V.

MicroRNA-based therapies in preclinical studies used for cardiomyocytes protection and proliferation

microRNA	Studied therapeutic agent	Subject to study	Activity/significance/side-effects	Reference
miR-195	Anti-miR-195 regulates anti-apoptotic genes, can decrease apoptosis after ACS	In vitro cultured myoblast	miR-195 inhibition did not affect cell ageing or rejuvenation of human skeletal muscle-derived stem/progenitor cells (SkMDS/PCs). It is unclear whether miR-195 antagonists can reverse cell senescence or the apoptotic rate	[153]
miR-199a	miR-199a was shown to directly target Clic5, which is involved in the proliferation of adult cardiomyocytes.	Mice	Although miR-199a has been reported to improve cardiac function, its prolonged administration led to lethal cardiac arrest	[143, 150]
miR-125b	miR-125b agonists	Mice	miR-125b overexpression efficiently attenuated cardiac function injury of heart failure mice by targeting BAK1 through inhibiting cardiomyocyte apoptosis, suggesting that the miR-125b/BAK1 axis might be a potential target for the diagnosis or treatment of HF	[152]
A cocktail of 4 microRNAs mimics (miR combo) miR-1, miR-133, miR-208, and miR-499	May be efficient in the induction of transformation of fibroblasts into induced cardiomyocytes (iCMs)	Adult human cardiac fibroblasts	The percentage of cTn-positive cells (former fibroblasts) 15 days after miR combo transfection was ∼11%, as evaluated by flow cytometry. A potential new strategy for myocardial regeneration after ACS	[114]
A cocktail of 4 microRNAs mimics (miR combo) miR-1, miR-133, miR-208, and miR-499	miR combo effectively reprograms fibroblasts of any mammalian species into cardiomyocytes	Cardiac fibroblasts of pig, dog and fetal human cardiac fibroblasts	miR combo reprograms pig, dog, and fetal human cardiac fibroblasts into cardiomyocyte-like cells that induce the expression of sarcomere and cardiac ion channels. In a fetal human cardiac fibroblast model ∼10% of cells had cardiomyocyte-like properties 14 days after transfection. This study validates the miR combo as a potential therapeutic modality for myocardial regeneration following ACS	[158]