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

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.

Extracellular Endothelial Cell-Derived Vesicles: Emerging Role in Cardiac and Vascular Remodeling in Heart Failure

“…Interestingly, EVs significantly inhibited microRNA-21 degradation and thereby mediate the anti-apoptotic effect in cardiac myocytes and endothelial cells (53). It has been demonstrated that the paracrine inhibitory impact of CPC on both cardiac fibroblast activation and collagen synthesis continues through cross-talk between cardiac fibroblasts and CPC-derived EVs (54). Thus, CPC-derived EVs ensure cardiac protection through paracrine output regarding cardiac myocytes that is attributable to decreased production of pro-healing cytokines and increased anti-inflammatory and anti-fibrotic microRNAs (55).…”

Potential Applications of Extracellular Vesicles in Solid Organ Transplantation

“…Much evidence confirms the hypothesis that cardiac progenitor cells release pro-regenerative and anti-fibrotic EVs in response to hypoxic conditions [82,83], mainly due to their miRNA cargo [82]. Moreover, cardiac-progenitor-cell-derived EVs, released into their environment, can stimulate migration of endothelial cells [84] and inhibit both cardiac fibroblast activation and collagen synthesis [85].…”

Follistatin-like 1 promotes proliferation of matured human hypoxic iPSC-cardiomyocytes and is secreted by cardiac fibroblasts

“…Human fetal tissue was obtained following parental permission using standard informed consent procedures, and fcFBs were isolated as previously described. 73 …”