Hopes and Hurdles of Employing Mesenchymal Stromal Cells in the Treatment of Cardiac Fibrosis.

Sebastian Neuber,Maximilian Y Emmert,Timo Z Nazari-Shafti

doi:10.3390/ijms222313000

Abstract

Excessive cardiac fibrosis plays a crucial role in almost all types of heart disease. Generally, cardiac fibrosis is a scarring process triggered in response to stress, injury, or aging and is characterized by the accumulation of activated myofibroblasts that deposit high levels of extracellular matrix proteins in the myocardium. While it is beneficial for cardiac repair in the short term, it can also result in pathological remodeling, tissue stiffening, and cardiac dysfunction, contributing to the progression of heart failure, arrhythmia, and sudden cardiac death. Despite its high prevalence, there is a lack of effective and safe therapies that specifically target myofibroblasts to inhibit or even reverse pathological cardiac fibrosis. In the past few decades, cell therapy has been under continuous evaluation as a potential treatment strategy, and several studies have shown that transplantation of mesenchymal stromal cells (MSCs) can reduce cardiac fibrosis and improve heart function. Mechanistically, it is believed that the heart benefits from MSC therapy by stimulating innate anti-fibrotic and regenerative reactions. The mechanisms of action include paracrine signaling and cell-to-cell interactions. In this review, we provide an overview of the anti-fibrotic properties of MSCs and approaches to enhance them and discuss future directions of MSCs for the treatment of cardiac fibrosis.

Highlights

Cardiac fibrosis accompanies most cardiac pathological conditions and is a critical contributor to the progression of heart failure [1]
We summarize the anti-fibrotic characteristics of mesenchymal stromal cells (MSCs) and ways to stimulate them and discuss the challenges and opportunities of using MSCs to treat cardiac fibrosis
Cardiac fibrotic responses triggered by pathological and environmental stimuli include the recruitment and activation of myofibroblasts, which are critical to physiological cardiac repair in the short term, but these events can lead to unfavorable scarring and heart failure in the long term

Summary

Introduction

Cardiac fibrosis accompanies most cardiac pathological conditions and is a critical contributor to the progression of heart failure [1]. Uncontrolled and progressive ECM deposition can lead to increased stiffness of the heart, resulting in decreased ventricular filling (diastolic dysfunction) and ventricular contraction (systolic dysfunction), contributing to the development of heart failure [3] These characteristic morphological and functional changes that accompany the transition from a healthy to a failing heart are summarized by the term cardiac remodeling [4]. Induced pluripotent stem cell-derived progenitor cells have been investigated as a potential source for the regeneration of injured myocardium [11] All of these cell therapies have in common that during preclinical evaluation in rodent models of myocardial injury, therapeutic outcome measures, such as angiogenesis, reduction of cardiac fibrosis, and global myocardial function, were improved. We summarize the anti-fibrotic characteristics of MSCs and ways to stimulate them and discuss the challenges and opportunities of using MSCs to treat cardiac fibrosis

Cardiac Fibrosis

Anti-Fibrotic Characteristics of MSCs

Modification of MSCs for an Increased Anti-Fibrotic Response

Challenges and Future Prospects of MSCs for Anti-Fibrotic Therapy

Findings

Conclusions