Building an Artificial Cardiac Microenvironment: A Focus on the Extracellular Matrix

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.

Heart in a Dish: From Traditional 2D Differentiation Protocols to Cardiac Organoids

“…On the other hand, the micropatterning platform represents a valuable alternative to develop spatially organized multicellular structures. However, the contribution of batch-to-batch variable components of Matrigel along the differentiation should be carefully evaluated ( Pagliarosi et al, 2020 ) and substituted with well-defined synthetic molecules whenever possible ( Gjorevski et al, 2016 ). Unfortunately, the structural complexity of in vivo organs, such as the four cardiac chambers, valves, and inflow/outflow tract, cannot be faithfully recreated with these models.…”

Current Strategies for the Regeneration of Skeletal Muscle Tissue

“…Collagen, the major structural component of ECM, has been used extensively in muscle tissue engineering, where its biocompatibility and resorption make it an attractive choice [ 138 , 139 , 140 , 141 ]. Li and coworkers developed a myoblast-seeded vascularized collagen hydrogel scaffold and implanted it into a VML model consisting of a full-thickness, single muscle defect in the rat biceps femoris muscle to show the importance of vascularization in muscle recovery [ 142 ].…”

Isolation and Culture of Neonatal Murine Primary Cardiomyocytes

“…The primary cardiomyocytes require an extracellular matrix (ECM) coating to adhere onto the surface of culture dishes. The substrates on which the cardiomyocytes are grown play an important part in enhancing cell attachment, growth, and differentiation (Pagliarosi, Picchio, Chimenti, Messina, & Gaetani, 2020). ECM-based coating such as fibronectin provide cell-adhesive motifs, recognized by the integrins present on the surface of cardiomyocytes, to improve cell-matrix interactions and thus, aid in their attachment to the substrate (Ruoslahti, 1988;Terracio et al, 1991).…”