Abstract
The increased knowledge in cell signals and stem cell differentiation, together with the development of new technologies, such as 3D bioprinting, has made the generation of artificial tissues more feasible for in vitro studies and in vivo applications. In the human body, cell fate, function, and survival are determined by the microenvironment, a rich and complex network composed of extracellular matrix (ECM), different cell types, and soluble factors. They all interconnect and communicate, receiving and sending signals, modulating and responding to cues. In the cardiovascular field, the culture of stem cells in vitro and their differentiation into cardiac phenotypes is well established, although differentiated cardiomyocytes often lack the functional maturation and structural organization typical of the adult myocardium. The recreation of an artificial microenvironment as similar as possible to the native tissue, though, has been shown to partly overcome these limitations, and can be obtained through the proper combination of ECM molecules, different cell types, bioavailability of growth factors (GFs), as well as appropriate mechanical and geometrical stimuli. This review will focus on the role of the ECM in the regulation of cardiac differentiation, will provide new insights on the role of supporting cells in the generation of 3D artificial tissues, and will also present a selection of the latest approaches to recreate a cardiac microenvironment in vitro through 3D bioprinting approaches.
Highlights
The regulation of cell proliferation, differentiation, and function is influenced by several factors, such as signaling molecules, cell-cell interaction, and the extracellular matrix (ECM), which are collectively defined as the microenvironment
The most studied cell regulatory signals are mediated by growth factors (GFs) and soluble cues, widely used in ex vivo research to differentiate adult and embryonic stem cells (ESCs) into mature cells
Different ECM molecules can regulate stem cell behavior by direct interactions with integrin receptors expressed on the cellular membrane, by modulating tissue compliance and consequent cell response through the mechanosensing machinery, or through the binding of different GFs and their controlled spatiotemporal presentation to the neighboring cells
Summary
The regulation of cell proliferation, differentiation, and function is influenced by several factors, such as signaling molecules, cell-cell interaction, and the extracellular matrix (ECM), which are collectively defined as the microenvironment. Among their many functions in homeostasis, these factors play a fundamental role in tissue development, turnover, and repair. The increasing use of induced pluripotent stem cells (iPSCs) to obtain differentiated cell types requires particular attention on the signals regulating their biology This very specific microenvironment is commonly defined as the stem cell “niche,” and its understanding and modeling could boost advancements in the field of tissue engineering, and even subsequent in vivo therapeutic applications (Chimenti et al, 2017).
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