Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair

Abstract

Adult mammalian hearts respond to injury with scar formation and not with cardiomyocyte proliferation, the cellular basis of regeneration. Although cardiogenic progenitor cells may maintain myocardial turnover, they do not give rise to a robust regenerative response. Here we show that extracellular periostin induced reentry of differentiated mammalian cardiomyocytes into the cell cycle. Periostin stimulated mononucleated cardiomyocytes to go through the full mitotic cell cycle. Periostin activated alphaV, beta1, beta3 and beta5 integrins located in the cardiomyocyte cell membrane. Activation of phosphatidylinositol-3-OH kinase was required for periostin-induced reentry of cardiomyocytes into the cell cycle and was sufficient for cell-cycle reentry in the absence of periostin. After myocardial infarction, periostin-induced cardiomyocyte cell-cycle reentry and mitosis were associated with improved ventricular remodeling and myocardial function, reduced fibrosis and infarct size, and increased angiogenesis. Thus, periostin and the pathway that it regulates may provide a target for innovative strategies to treat heart failure.

Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism

“…Interestingly, undifferentiated adipogenic progenitor cells are a major source of ECM components in AT (Kubo, Kaidzu, Nakajima, Takenouchi, & Nakamura, 2000; Nakajima, Yamaguchi, Ozutsumi, & Aso, 1998), suggesting that alterations in progenitor cell function with increased age may contribute to homeostatic changes in the tissue matrix (Tchkonia et al, 2010). Periostin is a secreted factor and its binding integrin heterodimers has been shown to activate protein kinase B and the focal adhesion kinase‐mediated intracellular signaling (Idolazzi et al, 2017; Kuhn et al, 2007; Morra & Moch, 2011). …”

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

“…Instead, we observed that the effect of both cytokines combined was lower than either alone. Thus, as both proteins may utilize similar signaling pathways [15,17], it is possible that they compete, limiting their combined effect. Indeed, this important observation should be considered when designing new studies involving combination therapies.…”

“…In addition to mediators of angiogenesis, the list of potential therapeutics for cardiac regeneration has continued to grow, and the use of factors involved in cardiac development, stem cell homing, cardiac differentiation/proliferation, or direct cardioprotection could lead to novel approaches for repairing damaged heart (reviewed in [4]). In this regard, in vitro studies have shown that adult cardiomyocytes do not proliferate under resting conditions, but may divide in response to extracellular mitogens, such as periostin [15], acidic fibroblast growth factor (FGF1) [16], and neuregulin-1 (NRG1) [17]. These findings have supported a new paradigm, which suggests that the heart might be capable of repair and regrowth in response to extracellular mitogens.…”

Functional role of periostin in development and wound repair: implications for connective tissue disease

“…Periostin has been observed to increase the number of cardiomyocytes actively replicating DNA in rats after myocardial infarction (Kuhn et al 2007). In particular, periostin is expressed by cardiac fibroblasts where it interacts with integrins on cells likely modulating their behaviour during the remodeling process following infarct (Shimazaki et al 2008).…”