The Hippo Pathway in Cardiac Regeneration and Homeostasis: New Perspectives for Cell-Free Therapy in the Injured Heart

Abstract

Intractable cardiovascular diseases are leading causes of mortality around the world. Adult mammalian hearts have poor regenerative capacity and are not capable of self-repair after injury. Recent studies of cell-free therapeutics such as those designed to stimulate endogenous cardiac regeneration have uncovered new feasible therapeutic avenues for cardiac repair. The Hippo pathway, a fundamental pathway with pivotal roles in cell proliferation, survival and differentiation, has tremendous potential for therapeutic manipulation in cardiac regeneration. In this review, we summarize the most recent studies that have revealed the function of the Hippo pathway in heart regeneration and homeostasis. In particular, we discuss the molecular mechanisms of how the Hippo pathway maintains cardiac homeostasis by directing cardiomyocyte chromatin remodeling and regulating the cell-cell communication between cardiomyocytes and non-cardiomyocytes in the heart.

Keywords: Hippo pathway; cardiac regeneration; chromatin reprogramming; immune response; proliferation; tissue homeostasis.

Figure 1

Overview of the Hippo pathway. The canonical Hippo signaling pathway is a complex network of proteins: mammalian sterile 20-like (MST) kinases 1/2, the adaptor proteins Salvador homolog 1 (SAV1), large tumor suppressor (LATS) kinases 1/2, Mps one binder kinase activator protein (MOB1), the downstream transcription cofactors Yes-associated protein 1 (YAP1) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ, also known as WWTR1). When Hippo signaling is on (shown in red), kinases MST1/2 and SAV1 complex, phosphorylate and activate kinases LATS1/2. LATS1/2 interacts with the adaptor MOB1 to phosphorylate YAP and its analog TAZ. YAP/TAZ undergo ubiquitination and degradation after phosphorylation. When Hippo signaling is off (shown in green), YAP/TAZ as transcriptional co-activators translocate into the nucleus and interact with TEA domain family members (TEADs) and other co-factors such as SMAD family members (SMADs), β-Catenin, pituitary homeobox 2 (PITX2), forkhead box protein O1 (FOXO1), T-box transcription factor TBX5 and Runt-related transcription factor 1/2 (RUNX1/2) to regulate gene transcription for cellular proliferation, regeneration, dedifferentiation, apoptosis and chromatin reprogramming. Transcription cofactor vestigial-like protein 4 (VGLL4) competes directly with YAP for the binding of TEADs in the nucleus [56,57,70]. Hippo pathway activity also can be regulated by several upstream proteins such as kidney and brain expressed protein (KIBRA), neurofibromin 2 (NF2), FERM domain-containing protein 6 (FRMD6), mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), striatin-interacting phosphatases and kinases (STRIPAK), serine/threonine-protein kinase 25 (STK25), Ras-associated domain family 1 isoform A (RASSF1A), thousand-and-one amino acid kinases 1/3 (TAOK1/3), P2Y₂ nucleotide receptor (P2Y₂R), protocadherin Fat4 (FAT4) and G-protein-coupled receptor signaling (GPCR). PKA, protein kinase A; AMOTL1, angiomotin-like protein 1.

Figure 2

The role of the Hippo pathway in heart regeneration and homeostasis. The Hippo pathway plays different roles in different cardiac cell types. When Hippo signaling is on (shown in red), it maintains heart homeostasis and inhibits CM apoptosis and activated CFs. After an injury, the damaged area in the heart consists of dead cardiomyocytes, activated cardiac fibroblasts, extracellular matrix (ECM), and immune cells including macrophages and T-regulatory (Treg) cells. When the heart is injured, the homeostasis of the heart is destroyed. Damage signals induce an immune response that activates resident macrophages, which release pro-inflammatory cytokines to induce inflammation and fibrosis. Resting cardiac fibroblasts induced into activated CFs and myofibroblasts, then activate CFs which promotes fibrosis in the damaged area. Cardiac fibroblasts activation also can be achieved through inhibition of the Hippo pathway. In cardiomyocytes, Yap activation induces cardiomyocytes to re-enter the cell cycle and proliferate when Hippo signaling is off (shown in green). YAP5SA overexpression promotes the generation of new cardiomyocytes and reorganizes chromatin accessibility to a proliferative fetal-like state. In epicardial cells, the Hippo pathway promotes the secretion of cytokines such as interferon-γ (IFNγ), which recruits T-regulatory (Treg) cells. Treg cells inhibit inflammation and fibrosis, promote cardiac repair and revascularization.