Paracrine mechanisms in adult stem cell signaling and therapy

Abstract

Animal and preliminary human studies of adult cell therapy following acute myocardial infarction have shown an overall improvement of cardiac function. Myocardial and vascular regeneration have been initially proposed as mechanisms of stem cell action. However, in many cases, the frequency of stem cell engraftment and the number of newly generated cardiomyocytes and vascular cells, either by transdifferentiation or cell fusion, appear too low to explain the significant cardiac improvement described. Accordingly, we and others have advanced an alternative hypothesis: the transplanted stem cells release soluble factors that, acting in a paracrine fashion, contribute to cardiac repair and regeneration. Indeed, cytokines and growth factors can induce cytoprotection and neovascularization. It has also been postulated that paracrine factors may mediate endogenous regeneration via activation of resident cardiac stem cells. Furthermore, cardiac remodeling, contractility, and metabolism may also be influenced in a paracrine fashion. This article reviews the potential paracrine mechanisms involved in adult stem cell signaling and therapy.

Figure 1. Proposed mechanisms of adult stem cell action in cardiac repair

Transdifferentiation and cell fusion of transplanted stem cells lead to cardiac regeneration and vasculogenesis. Paracrine effects can positively influence many processes, among them cardiomyogenesis and neovascularization (see text for details). Cardiac regeneration, vasculogenesis and paracrine effects lead to cardiac repair.

Figure 2. Paracrine-autocrine mechanisms in stem cell signaling and therapy

ASCs release biologically active substances in a temporal and spatial manner in response to specific environmental stimuli such as ischemia. These factors influence the microenvironment by exerting paracrine actions on different cell types leading to tissue protection, repair and regeneration. The putative factors may also exert autocrine actions modulating the biology of stem cells including self-renewal and proliferation.

Figure 3. Proposed factors and signalling pathways involved in stem cell-mediated myocardial protection, , –

It has been shown that ASCs mediate cardioprotection by producing and releasing soluble mediators with known cytoprotective properties. Most of these factors act through the activation of the pro-survival PI-3 kinase/Akt pathway. Factors like FGF-2 and EPO can activate the protein kinase C pathway, which has been shown to mediate cardioprotection. Interleukin 11 (IL11) also activates survival signalling cascades in PI3K/Akt and ERK1/2-STAT3 dependent fashion. The mechanisms of action through which Sfrp2 and TB4 lead to cardioprotection are partially undetermined and need to be further clarified. Finally, other factors and pathways are certainly involved but are still unidentified. Abbreviations: IL11, interleukin 11; HGF, hepatocyte growth factor; IGF-1, insulin growth factor 1; VEGF, vascular endothelial growth factor; EPO, erythropoietin; FGF-2, fibroblast growth factor-2; TB4, thymosin beta 4; GF, growth factor; C, cytochrome c; GLUT, glucose transporter; VDAC, voltage-dependent anion channel.

Figure 4. Mechanisms involved in neovascularization

In contrast to the embryonic heart vasculature, the adult heart vessels are quiescent. Only when under stress or in the presence of pathologic conditions, like myocardial infarction, the coronary vascular bed expands. ASCs are involved in postnatal neovascularization which encompasses 3 different mechanisms: the first is referred to as postnatal vasculogenesis, that consists in the assembly of new blood vessels by fusion and differentiation of endothelial precursor cells originating from the bone marrow. The second mechanism is angiogenesis and consists in the sprouting of new vessels from pre-existing vessels. The third mechanism is collateral enlargement and muscolarization, namely arteriogenesis. The release of proangiogenic and proarteriogenic factors by transplanted stem cells positively influences neovascularization in a paracrine fashion.

Figure 5. Mechanisms involved in cardiac regeneration

Potentially, ASCs may lead to cardiac regeneration via different mechanisms. Transdifferentiation into newly formed cardiomyocytes has been the first proposed way. Cell fusion of stem cells with native cardiomyocytes represents a second possibility but the biological meaning of this event remains unclear. Finally, soluble paracrine factors released by the stem cells may induce activation, migration and differentiation of CSCs and/or enhance proliferation of resident cardiomyocytes.