Epicardial FSTL1 reconstitution regenerates the adult mammalian heart

Abstract

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.

Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload

“…Comparison of KEGG cell cycle pathway regulators in RNA-seq data sets from sham WT and sham D2 hearts 3 weeks after surgery identified 11 differentially regulated genes ( Figure 9 and Supplemental Table 1). The data set was also interrogated for genes previously implicated in regulating cardiomyocyte cell cycle activity, including HIPPO pathway members (i.e., YAP and TAZ) (18), ALMS1 (Alstroem's 1) (19), FGF1 (20), FGF2 (21), WNT/β-catenin (22), neuregulin (23), ERBB2 (a neuregulin coreceptor) (24), PITX2 (25), Meis1 (26), Notch/Jagged1 (27), periostin (28), agrin (29), follistatin-like 1 (FSTL1) (30), and TERT (31). Of these, only PITX2 expression was observed to be increased in D2-sham hearts versus WT-sham hearts (Supplemental Table 1).…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…The secreted signaling inhibitor follistatin-like 1 (FSTL1) is upregulated after cardiac injury and has been flagged as a biomarker of acute coronary syndrome (Alteköester and Harvey, 2015). In a recent study, the epicardial isoform of FSTL1 was delivered to the heart after myocardial infarction via a collagen patch sutured to the infarct surface (Wei et al, 2015). This treatment increased animal survival, vascularization and cardiac function, while decreasing adverse remodeling.…”

Building and re-building the heart by cardiomyocyte proliferation

“…In any case, the upstream factors that induce the expression of Nrg1, and the downstream pathways through which its activity is mediated, require elucidation. Additionally, a recent report indicates that in adult mammals, follistatin-like 1 (Fstl1) might act to improve cardiomyocyte survival and/or proliferation after MI preferentially if produced from the epicardium (Wei et al, 2015).…”