Harnessing Mechanosensation in Next Generation Cardiovascular Tissue Engineering

Abstract

The ability of the cells to sense mechanical cues is an integral component of "social" cell behavior inside tissues with a complex architecture. Through "mechanosensation" cells are in fact able to decrypt motion, geometries and physical information of surrounding cells and extracellular matrices by activating intracellular pathways converging onto gene expression circuitries controlling cell and tissue homeostasis. Additionally, only recently cell mechanosensation has been integrated systematically as a crucial element in tissue pathophysiology. In the present review, we highlight some of the current efforts to assess the relevance of mechanical sensing into pathology modeling and manufacturing criteria for a next generation of cardiovascular tissue implants.

Keywords: cardiac regeneration; mechanosensing; tissue engineering.

Figure 1

An example of “intelligent hydrogel” application for treating myocardial infarction. Hydrogels with defined mechanical compliance could be used as cell-free scaffolds, functionalized with pharmacological drugs or miRNAs decreasing ECM synthesis and cardiac myofibroblast activation (e.g., miR-29, miR-133 or drugs interfering with YAP transcriptional activity) or inducing CM reactivation of cell cycle to promote tissue regeneration (e.g., collagen/elastin cross-linking inhibitors, YAP/HIPPO signaling inhibitors).

Figure 2

In situ tissue engineered heart valve (TEHV) approach. By the use of this approach, the wound healing cascade—which characterize valve regeneration process—is harnessed for repopulating cell-free synthetic scaffold with living cells. A specific anisotropic structure of the scaffold in combination with specific therapeutic molecules involved in cell mechanosensing (e.g., YAP inhibitors, drugs interfering with stress fibers tensioning) drive towards a scaffold repopulation with proliferative non-activated cells able to synthetize new ECM components (collagen (blue), elastin (green) and GAG (orange)) and thus realize a functional heart valve tissue.

Figure 3

Mechanical properties (e.g., burst pressure, stiffness), surface modifications (e.g., matrix topography patterns, functionalization with specific anti-fibrotic miRNAs) and the selection of the proper biomaterial (e.g., hybrid scaffold, silk) play a crucial role in promoting maturation of vascular tissue engineered constructs.