Cardiac progenitor cell therapy: mechanisms of action

Abstract

Heart failure (HF) is an end-stage of many cardiac diseases and one of the main causes of death worldwide. The current management of this disease remains suboptimal. The adult mammalian heart was considered a post-mitotic organ. However, several reports suggest that it may possess modest regenerative potential. Adult cardiac progenitor cells (CPCs), the main players in the cardiac regeneration, constitute, as it may seem, a heterogenous group of cells, which remain quiescent in physiological conditions and become activated after an injury, contributing to cardiomyocytes renewal. They can mediate their beneficial effects through direct differentiation into cardiac cells and activation of resident stem cells but majorly do so through paracrine release of factors. CPCs can secrete cytokines, chemokines, and growth factors as well as exosomes, rich in proteins, lipids and non-coding RNAs, such as miRNAs and YRNAs, which contribute to reparation of myocardium by promoting angiogenesis, cardioprotection, cardiomyogenesis, anti-fibrotic activity, and by immune modulation. Preclinical studies assessing cardiac progenitor cells and cardiac progenitor cells-derived exosomes on damaged myocardium show that administration of cardiac progenitor cells-derived exosomes can mimic effects of cell transplantation. Exosomes may become new promising therapeutic strategy for heart regeneration nevertheless there are still several limitations as to their use in the clinic. Key questions regarding their dosage, safety, specificity, pharmacokinetics, pharmacodynamics and route of administration remain outstanding. There are still gaps in the knowledge on basic biology of exosomes and filling them will bring as closer to translation into clinic.

Keywords: Adult cardiac progenitor cells; Cardiac regeneration; Exosomes; Non-coding RNAs.

Fig. 1

General routes of influence of cardiac progenitor cells on heart regeneration after myocardial infarction. Cardiac progenitor cells may act via three main mechanisms to contribute to cardiac repair after damage. They include: direct differentiation into cardiac cells such as cardiomyocytes, endothelial cells and vascular smooth muscle cells; activation of cardiac stem cells to differentiate into different cardiac cells; and paracrine effects by which CPCs promote angiogenesis and cardioprotection while suppressing fibrosis and inflammation. Preclinical and clinical studies show that transplantation of cardiac progenitor cells and administration of their acellular products lead to improvement in functional and structural parameters of the heart after myocardial damage (Created with BioRender.com)

Fig. 2

Paracrine mechanisms of action of cardiac progenitor cells on heart-derived cells. Cardiac progenitor cells exert paracrine effects on cardiac stem cells, cardiomyocytes, cardiac fibroblasts, immune cells and endothelial cells contributing to repair of myocardium after injury. Two main characterized routes of paracrine action include secretion of proteins or release of exosomes rich in protein, DNA, RNA and lipid cargoes. Abbreviations: ANG-1 - Angiopoietin 1, bFGF - Basic Fibroblast Growth Factor, HGF - Hepatocyte Growth Factor, IGF-1 - Insulin-like Growth Factor 1, IGFBPs – Insulin-like Growth Factor Binding Proteins, PAPP-A - pregnancy-associated plasma protein-A, SCF - Stem Cell Factor, SDF-1α - Stromal cell Derived Factor 1α, VEGFA - Vascular Endothelial Growth Factor A, PDGFB - Platelet Derived Growth Factor subunit B (Created with BioRender.com)

Fig. 3

Non-coding RNAs enriched in cardiac progenitor cell-derived exosomes promote heart regeneration after injury. CPC-derived exosomes which are rich in cardioprotective non-coding RNAs, including miRNAs and YRNAs, can be administered via intramyocardial injection or intracoronary infusion to the damaged heart and exert beneficial effects including reduction of fibrosis and infarct mass, reduced inflammation and cardiac hypertrophy and promotion of cardiomyocytes survival, angiogenesis and improvement of cardiac function Abbreviations: CPCs – cardiac progenitor cells, ncRNAs – non-coding RNAs (Created with BioRender.com)