In Vitro Mechanical Stimulation to Reproduce the Pathological Hallmarks of Human Cardiac Fibrosis on a Beating Chip and Predict The Efficacy of Drugs and Advanced Therapies

Abstract

Cardiac fibrosis is one of the main causes of heart failure, significantly contributing to mortality. The discovery and development of effective therapies able to heal fibrotic pathological symptoms thus remain of paramount importance. Micro‐physiological systems (MPS) are recently introduced as promising platforms able to accelerate this finding. Here a 3D in vitro model of human cardiac fibrosis, named uScar, is developed by imposing a cyclic mechanical stimulation to human atrial cardiac fibroblasts (AHCFs) cultured in a 3D beating heart‐on‐chip and exploited to screen drugs and advanced therapeutics. The sole provision of a cyclic 10% uniaxial strain at 1 Hz to the microtissues is sufficient to trigger fibrotic traits, inducing a consistent fibroblast‐to‐myofibroblast transition and an enhanced expression and production of extracellular matrix (ECM) proteins. Standard of care anti‐fibrotic drugs (i.e., Pirfenidone and Tranilast) are confirmed to be efficient in preventing the onset of fibrotic traits in uScar. Conversely, the mechanical stimulation applied to the microtissues limit the ability of a miRNA therapy to directly reprogram fibroblasts into cardiomyocytes (CMs), despite its proved efficacy in 2D models. Such results demonstrate the importance of incorporating in vivo‐like stimulations to generate more representative 3D in vitro models able to predict the efficacy of therapies in patients.

An iPSC-derived bio-inspired scaffold modelling the structure and the effects of extracellular matrix in cardiac fibrosis

“…The most recent attempts at modelling cardiac fibrosis rely on microfluidic platforms combining biochemical and mechanical stimuli to induce cardiac fibroblasts activation to myofibroblasts [ 91 ] , or multicellular systems based on the co-culture of cardiomyocytes and cardiac fibroblasts of various origin [ 92, 93 ] .…”

Modifying miRs for effective reprogramming of fibroblasts to cardiomyocytes

“… 40 Thus, there is a possibility by combining a modified miR combo with an optimized carrier that reprogramming efficacy could be improved still further. With respect to moving 5′ppp-miR combo forward clinically, future testing could be carried out in cardiac tissue mimics, 41 which represent a different approach to testing and screening drugs prior to pre-clinical models such as the pig.…”