Cells used in Cardiac Tissue Engineering

Crucial concerns in cardiac tissue engineering are the identification of suitable cell sources and the characterization of the composition of cell populations used in engineering high-fidelity in-vitro constructs. For tissue engineering purposes, the heart may be divided into two functions: mechanical, and electrical. Arguably, the main mechanical function (contractility) is mediated by cardiac myocytes, while the electrical activities of the heart are mediated by specific neurons. In the past, the main focus of cardiac tissue engineering has been on the myocytes only. These cells are mechanically and electrically active, have high metabolic rates, and are characterized by prolonged survival. However, under certain pathological conditions, they undergo hypertrophy or a variety of other diseases and defects causing a decrease in the contractile properties ofthe heart muscle [96]. Therefore, the important design criterion for cardiac engineered tissues is to have a template scaffold that facilitates induction and maintenance of the physiological properties mentioned above in order to ensure proper myocyte development and function towards in-vivo implantation.

The restoration of heart function by replacement of the diseased myocardium with functional cardiac myocytes is an attractive strategy. Indeed, cardiac myocytes and other cell types have been successfully implanted into the hearts of larger animals [97], improving contractile function after myocardial infarction [46].

However, a major limitation ofcardiac tissue engineering is the inability ofcardiac myocytes to proliferate [98]. Since cardiac myocytes are terminally differentiated cells, they cannot compensate for cell loss that occurs during myocardial infarction or chronic heart failure. Endothelial cells, fibroblasts, smooth muscle cells, and neuronal cells comprise some 70% of the total cell number in the working myocardium [99], and play important roles in cardiac tissue development and function [100, 101]. The exact contribution of each single cell type to tissue-formation has not yet been thoroughly analyzed, but in theory the formation of a 3D cardiac tissue-like construct needs to consider the presence of both cardiac myocytes and non-myocytes, ideally at similar ratios as in their native physiological environment [93].

Although current tissue engineering approaches mainly utilize myocytes, it appears that primary cardiac cells will never be used as a cell source for cardiac tissue engineering in patients [93]. In contrast, embryonic and adult stem cells demonstrate significant proliferation capacity and provide great hope for cardiac replacement therapy [102, 103]. The capacity of murine embryonic stem (ES) cells to differentiate into cardiac myocytes upon homing to the heart tissue has been demonstrated previously [104]. Given the current debate about ES cells, autologous, post-embryonic stem cells derived from umbilical cord blood, bone marrow, or from adult tissues would in theory be the ideal choice. Provided that some recent indications for the unexpected plasticity of adult stem cells can indeed be validated, post-embryonic stem cells would be excellent candidates for use in tissue engineering [105]. The observation that circulating or injected adult stem cells home into the injured myocardium and locally transdifferentiate into cardiac myocytes [106] is of significant interest because it opens the way to mimic those conditions in vitro. Recent in-vivo studies have also demonstrated that the local cardiac environment might drive the differentiation of implanted immature cardiac myocytes [107]. The conditions required for stem cells to efficiently differentiate into mature myocytes are not yet clear, and require elucidation.

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