Abstract
The irreversible loss of functional cardiomyocytes (CMs) after myocardial infarction (MI) represents one major barrier to heart regeneration and functional recovery. The combination of different cell sources and different biomaterials have been investigated to generate CMs by differentiation or reprogramming approaches although at low efficiency. This critical review article discusses the role of biomaterial platforms integrating biochemical instructive cues as a tool for the effective generation of functional CMs. The report firstly introduces MI and the main cardiac regenerative medicine strategies under investigation. Then, it describes the main stem cell populations and indirect and direct reprogramming approaches for cardiac regenerative medicine. A third section discusses the main techniques for the characterization of stem cell differentiation and fibroblast reprogramming into CMs. Another section describes the main biomaterials investigated for stem cell differentiation and fibroblast reprogramming into CMs. Finally, a critical analysis of the scientific literature is presented for an efficient generation of functional CMs. The authors underline the need for biomimetic, reproducible and scalable biomaterial platforms and their integration with external physical stimuli in controlled culture microenvironments for the generation of functional CMs.
Highlights
Myocardial infarction (MI) is caused by the obstruction of coronary arteries, resulting in the death of approximately 1 billion cardiomyocytes (CMs) in the left ventricle within a few hours, acute inflammation and degradation of the cardiac extracellular matrix (ECM), with the formation of a fibrotic scar
Zhou et al have shown that induced pluripotent stem cells (iPSCs)-CMs generated from mouse cardiac fibroblasts displayed increased expression of genes related to glycolysis, whereas CMs induced by direct reprogramming of fibroblasts showed higher expression of genes involved in fatty acid-β oxidation [66]
Sa et al have investigated the effect of fibronectin/laminin combinations on the differentiation of Embryonic Stem Cells (ESCs) time and proposed a mechanism based on integrin-mediated MEK/ERK signalling and direct cell-towithout using any induction molecule: they found out that fibronectin/laminin 70/30 caused the highest cell communication from distinct cells respectively expressing the laminin and fibronectin integrin percentage of differentiation into CMs positive for Nkx2.5 and cardiac troponin I (cTnI) after 14 days culture time and proposed receptors
Summary
Myocardial infarction (MI) is caused by the obstruction of coronary arteries, resulting in the death of approximately 1 billion cardiomyocytes (CMs) in the left ventricle within a few hours, acute inflammation and degradation of the cardiac extracellular matrix (ECM), with the formation of a fibrotic scar. Injectable hydrogels and cell therapy are infarcted under investigation therapeutic of myocardial contractility, through the repopulation of the area with as beating approaches for myocardial [2,6,8,9]. In the last decade, emerging studies have raised a new intriguing possibility for myocardial regeneration, represented by the direct reprogramming of fibroblasts into CMs. Considering the abundance of cardiac fibroblasts in the heart, the possibility for their direct reprogramming is expected to revolutionize therapies for myocardial regeneration by the direct conversion of dysfunctional fibrotic scar into contractile myocardial tissue [12,13,14,15,16]. We will critically discuss the key role of biomaterials in the functional maturation of CMs
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