Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis

Abstract

A new era has begun in the treatment of ischemic disease and heart failure. With the discovery that stem cells from diverse organs and tissues, including bone marrow, adipose tissue, umbilical cord blood, and vessel wall, have the potential to improve cardiac function beyond that of conventional pharmacological therapy comes a new field of research aiming at understanding the precise mechanisms of stem cell-mediated cardiac repair. Not only will it be important to determine the most efficacious cell population for cardiac repair, but also whether overlapping, common mechanisms exist. Increasing evidence suggests that one mechanism of action by which cells provide tissue protection and repair may involve paracrine factors, including cytokines and growth factors, released from transplanted stem cells into the surrounding tissue. These paracrine factors have the potential to directly modify the healing process in the heart, including neovascularization, cardiac myocyte apoptosis, inflammation, fibrosis, contractility, bioenergetics, and endogenous repair.

Figure 1

Actions of stem cell derived paracrine factors on the heart. Stem cells transplanted into the myocardium release numerous factors that may act in an autocrine manner or paracrine manner to modulate the implanted cells themselves, or the endogenous cells of the heart, including cardiac myocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, and cardiac stem cells. These factors include a variety of growth factors, cytokines, and extracellular matrix proteins that may lead to upregulation of several endogenous growth factors, cytokines, and extracellular matrix proteins, thereby tightly regulating neovascularization, protection against cell death, inflammation, fibrosis, contractility, bioenergetics, and endogenous repair. Regulation of these processes, either singly or in combination, by stem cell transplantation ultimately leads to improvement in left ventricular function following myocardial infarction. Future research in discovering novel stem-derived paracrine factors and their precise mechanistic roles in heart repair and fibrosis may ultimately lead to the generation of novel therapeutic agents for the treatment of heart failure.