title: Complement anaphylatoxins C3a and C5a induce a failing regenerative program in cardiac resident cells. Evidence of a role for cardiac resident stem cells other than cardiomyocyte renewal.
abstract: Cardiac healing, which follows myocardial infarction, is a complex process guided by intricate interactions among different components. Some resident cell populations with a potential role in cardiac healing have already been described in cardiac tissues. These non-cardiomyocyte cell subsets, globally described as cardiac pluripotent/progenitor cells (CPCs), are able to differentiate into all three major cardiac cell lineages (endothelial, smooth muscle and cardiomyocyte cells) in experimental settings. Nevertheless, physiological cardiac healing results in a fibrous scar, which remains to be fully modelled experimentally. Since a role for complement anaphylatoxins (C3a and C5a) has been described in several regeneration/repair processes, we examined the effects that C3a and C5a exert on a defined population of CPCs. We found that C3a and C5a are able to enhance CPC migration and proliferation. In vitro studies showed that this effect is linked to activation of telomerase mRNA and partial preservation of telomere length, in an NFκB-dependent manner. In addition, anaphylatoxin signalling modulates the CPC phenotype, increasing myofibroblast differentiation and reducing endothelial and cardiac gene expression. These findings may denote that C3a and C5a are able to maintain/increase the cardiac stem cell pool within the heart, whilst simultaneously facilitating and modulating resident cell differentiation. We found that this modulation was directed towards scar forming cells, which increased fibroblast/myofibroblast generation and suggests that both these anaphylatoxins could play a relevant role in the damage-coupled activation of resident cells, and regulation of the cardiac healing process after injury.
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, 28029 Spain.
authors.forename: David
authors.initials: D
authors.lastname: Lara-Astiaso
authors.forename: Alberto
authors.initials: A
authors.lastname: Izarra
authors.forename: Juan Camilo
authors.initials: JC
authors.lastname: Estrada
authors.forename: Carmen
authors.initials: C
authors.lastname: Albo
authors.forename: Isabel
authors.initials: I
authors.lastname: Moscoso
authors.forename: Enrique
authors.initials: E
authors.lastname: Samper
authors.forename: Javier
authors.initials: J
authors.lastname: Moncayo
authors.forename: Abelardo
authors.initials: A
authors.lastname: Solano
authors.forename: Antonio
authors.initials: A
authors.lastname: Bernad
authors.forename: Antonio
authors.initials: A
authors.lastname: Díez-Juan