Abstract
For tissue-engineering studies of the infarcted heart it is essential to identify a source of cells that may provide cardiomyocyte progenitors, which is easy to amplify, accessible in adults, and allowing autologous grafts. Preclinical studies have shown that human adipose-derived stem cells (ADSCs) can differentiate into cardiomyocyte-like cells and improve heart function in myocardial infarction. We have developed pharmacologically active microcarriers (PAMs) which are biodegradable and biocompatible polymeric microspheres conveying cells on their biomimetic surface, therefore providing an adequate three-dimensional (3D) microenvironment. Moreover, they can release a growth factor in a prolonged manner. In order to implement ADSCs and PAMs for cardiac tissue engineering we first defined the biomimetic surface by studying the influence of matrix molecules laminin (LM) and fibronectin (FN), in combination with growth factors present in the cardiogenic niche, to further enhance the in vitro cardiac differentiation of ADSCs. We demonstrated that LM increased the expression of cardiac markers (Nkx2.5, GATA4, MEF2C) by ADSCs after 2 weeks in vitro. Interestingly, our results suggest that the 3D support provided by PAMs with a LM biomimetic surface (LM-PAMs) further enhanced the expression of cardiac markers and induced the expression of a more mature contractile protein, cardiac troponin I, compared with the 2D differentiating conditions after only 1 week in culture. The enrichment of the growth-factor cocktail with TGF-β1 potentiated the cardiomyogenic differentiation. These results suggest that PAMs offering a LM biomimetic surface may be efficiently used for applications combining adult stem cells in tissue-engineering strategies of the ischemic heart.
Highlights
Myocardial infarction (MI) constitutes the first cause of morbidity and mortality in developed countries
Adipose derived-stem cells (ADSCs) cardiac commitment with the cocktail of growth factors (GFs) We studied the expression of the main transcription factors that initiate the differentiation pathway toward the cardiomyocyte lineage (GATA4, Nkx2.5, myocyte enhancer factor 2C (MEF2C))[45,46,47] and the expression of specific cardiac proteins in the ADSCs treated with the GF cocktail within 2 weeks
After the GF treatment for 2 weeks GATA binding protein 4 (GATA4) was highly expressed (29-fold increase compared with the first week) while the mRNA level of MEF2C did not significantly increase and Nkx2.5 was not expressed at all [Fig. 1(A)]
Summary
Myocardial infarction (MI) constitutes the first cause of morbidity and mortality in developed countries. After MI, a necrotic and poorly vascularized zone appears, damaged cardiomyocytes are removed by macrophages and gradually replaced by scar tissue due to the limited intrinsic regenerative capacity of the heart. Current treatments present certain limitations, for heart tissue repair, in recent years, cell-based therapies have attracted considerable interest as an alternative way of achieving cardiac repair. Transplantation of ADSCs after MI has shown benefits on cardiac function through vessel formations, improvement in left ventricular ejection fraction (LVEF) and diminution of scar area.[11,12,13,14] the low percentage of living cells remaining in the tissue[12] and the limited cardiac differentiation after transplantation,[11,15] are problems that need to be taken into consideration for future studies
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