Anti-fibrotic Effects of Cardiac Progenitor Cells in a 3D-Model of Human Cardiac Fibrosis.

Tom C L Bracco Gartner,Linda W Van Laake,Joost P G Sluijter,Janine C Deddens,Willem J L Suyker,Emma A Mol,Marina Magin Ferrer,Pieter A Doevendans,Carlijn V C Bouten,Ali Khademhosseini,Jesper Hjortnaes

doi:10.3389/fcvm.2019.00052

Abstract

Cardiac fibroblasts play a key role in chronic heart failure. The conversion from cardiac fibroblast to myofibroblast as a result of cardiac injury, will lead to excessive matrix deposition and a perpetuation of pro-fibrotic signaling. Cardiac cell therapy for chronic heart failure may be able to target fibroblast behavior in a paracrine fashion. However, no reliable human fibrotic tissue model exists to evaluate this potential effect of cardiac cell therapy. Using a gelatin methacryloyl hydrogel and human fetal cardiac fibroblasts (hfCF), we created a 3D in vitro model of human cardiac fibrosis. This model was used to study the possibility to modulate cellular fibrotic responses. Our approach demonstrated paracrine inhibitory effects of cardiac progenitor cells (CPC) on both cardiac fibroblast activation and collagen synthesis in vitro and revealed that continuous cross-talk between hfCF and CPC seems to be indispensable for the observed anti-fibrotic effect.

Highlights

Chronic heart failure (CHF) is the leading cause of cardiovascular death, with a 5-year mortality rate of 50% [1]
We aimed to construct a human model of cardiac fibrosis using human fetal cardiac fibroblasts (hfCF) and GelMA (Figure 1A). hfCF were isolated by enzymatic digestion of human fetal cardiac tissue
Immunofluorescent staining confirmed the fibroblast-like phenotype of hfCF as shown by protein expression of vimentin and fibroblast specific protein (FSP)

Summary

Introduction

Chronic heart failure (CHF) is the leading cause of cardiovascular death, with a 5-year mortality rate of 50% [1]. End stage heart failure is characterized by excessive collagen deposition caused by adverse cardiac remodeling. The remodeling process is suggested to be primarily mediated by cardiac fibroblasts (CF) [2,3,4], which are activated upon myocardial injury, undergoing a phenotypical switch to myofibroblasts. Myofibroblasts are characterized by their proliferative activity, increased contractile function as a result of alpha smooth muscle actin (α-SMA) expression, and increased extracellular matrix (ECM) production. These myofibroblasts fail to undergo apoptosis and remain constitutively active. Cardiac fibrosis leads to impaired diastolic function and electrophysiological abnormalities

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