Biomimetic Gelatin Nanofibrous Scaffolds for the Mechanical Modulation of Cardiac Pericyte Fate

Abstract

Congenital heart disease (CHD) is the most common and deadly congenital anomaly, accounting for up to 7.5% of all infant deaths. Survival in children born with CHD has improved dramatically over the past several decades, this positive trend being counterbalanced by the fact that more patients develop heart failure. Seminal data indicate an alteration of the extracellular matrix occurs with time in these hearts due to diffuse and abundant interstitial fibrosis. This results in an escalation in stiffness of the local microenvironment. However, the influence of matrix stiffness in regulating the function of resident human stromal cells has not been reported. The objective of this study was to determine the impact of stiffness on the antigenic and functional profile of cardiac pericytes (CPs) isolated from patients with CHD. To this aim, firstly, gelatin nanofibrous scaffolds with varying degree of stiffness using an in situ electrospinning technique were produced. The Young’s Modulus were assessed and then performed a comprehensive physicochemical characterisation of the scaffolds employing scanning electron microscopy, atomic force microscopy, and Fourier-transform infrared spectroscopy. This study next evaluated the changes induced by different scaffold stiffness on CPs morphology, antigenic profile, viability, proliferation, angiocrine activity, and induced differentiation. Results indicate that soft matrixes (Young’s modulus <0.3 MPa) with larger fiber diameter (~400 nm), increase CPs adhesion, proliferation, secretion of Angiopoietin 2, Vascular Endothelial Growth Factor A (VEGF A) and F-actin stress fiber formation upon induced differentiation into vascular smooth muscle cells. There was no effect of stiffness on CPs antigenic profile or viability. To the best of my knowledge, these data indicate for the first time that human CPs can be functionally influenced by subtle changes in matrix stiffness. The study elucidates the importance of mechanical/morphological cues in modulating stromal cell behaviour and the feasibility of exploiting matrix stiffness to increase key features instrumental to the CPs regenerative potential.

Date of Award	1 Oct 2019
Original language	English
Awarding Institution	University of Bristol
Supervisor	Sean A Davis (Supervisor), Bo Su (Supervisor) & Paolo R Madeddu (Supervisor)