Upstream regulation of the Hippo-Yap pathway in cardiomyocyte regeneration

Abstract

The response of the adult mammalian heart to injury such as myocardial infarction has long been described as primarily fibrotic scarring and adverse remodeling with little to no regeneration of cardiomyocytes. Emerging studies have challenged this paradigm by demonstrating that, indeed, adult mammalian cardiomyocytes are capable of completing cytokinesis albeit at levels vastly insufficient to compensate for the loss of functional cardiomyocytes following ischemic injury. Thus, there is great interest in identifying mechanisms to guide adult cardiomyocyte cell cycle reentry and facilitate endogenous heart regeneration. The Hippo signaling pathway is a core kinase cascade that functions to suppress the transcriptional co-activators Yap and Taz by phosphorylation and therefore cytoplasmic retention or phospho-degradation. This pathway has recently sparked interest in the field of cardiac regeneration as inhibition of Hippo kinase signaling or overdriving the transcriptional co-activator, Yap, significantly promotes proliferation of terminally differentiated adult mammalian cardiomyocytes and can restore function in failing mouse hearts. Thus, the Hippo pathway is an attractive therapeutic target for promoting cardiomyocyte renewal and cardiac regeneration. Although the core kinases and transcriptional activators of the Hippo pathway have been studied extensively over the last twenty years, the regulatory inputs of this pathway, particularly in vertebrates, are poorly understood. Recent studies have elucidated several upstream regulatory inputs to the Hippo pathway in adult mammalian cardiomyocytes that influence cell proliferation and heart regeneration. Considering upstream inputs to the Hippo pathway are thought to be context and cell type specific, targeting these various components could serve as a therapeutic approach for refining Hippo-Yap signaling in the heart. Here, we provide an overview of the emerging regulatory inputs to the Hippo pathway as they relate to mammalian cardiomyocytes and heart regeneration.

Role of YAP/TAZ in Cell Lineage Fate Determination and Related Signaling Pathways

“…Upstream signaling pathways regulating YAP/TAZ activity have been shown to mediate cellular interactions with a broad range of microenvironmental factors including (i) soluble bioactive ligands ( Yu et al, 2012 ; Cai and Xu, 2013 ; Chen and Harris, 2016 ; Yang et al, 2019 ), (ii) biomechanical cues ( Dupont et al, 2011 ; Kim et al, 2011 ; Nardone et al, 2017 ; Pardo-Pastor et al, 2018 ), (iii) energy, osmotic and hypoxic stress ( DeRan et al, 2014 ; Ma et al, 2015 ; Mo et al, 2015 ), and (iv) inflammation and tissue injury ( Gregorieff et al, 2015 ; Kim H. B. et al, 2017 ; Choi et al, 2018 ; Flinn et al, 2019 ), via a diverse array of surface receptors, cytoskeletal elements and cytosolic signaling proteins, as illustrated in Figure 2 . Hence, by manipulating YAP/TAZ signaling, we can control how stem/progenitor cells change their phenotype in response to external stimulation and microenvironmental cues.…”

miR-199a Overexpression Enhances the Potency of Human Induced-Pluripotent Stem-Cell–Derived Cardiomyocytes for Myocardial Repair

“…Experiments in neonatal rat cardiomyocytes have shown that miR-199a directly targets the YAP inhibitory kinase TAOK1 and the E3 ubiquitin ligase β-TrCP, thereby impeding YAP degradation and promoting the translocation of YAP into the nucleus (Torrini et al, 2019). Furthermore, observations in mice suggest that increases in YAP abundance and nuclear localization are sufficient to induce the proliferation of cardiac cells and to improve cardiac performance after MI (Flinn, Link, and O'Meara 2020). Here, we found that the ratio of Serine-127-phosphorated YAP (p-YAP) to total YAP abundance was significantly lower (Figures 2A, B), while nuclear YAP levels were significantly greater, in AAV6-miR-199a-than in AAV6-FIGURE 3 | AAV6miR-199a-tranduced hiPSC-CMs were more potent than AAV6-Control-transduced hiPSC-CMs for myocardial recovery in a mouse MI model.…”

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

“…In addition to TEADs, studies have identified many other YAP/TAZ co-factors such as SMAD family members (SMADs) [ 41 , 42 , 43 , 44 , 45 , 46 ], β-Catenin [ 20 ], pituitary homeobox 2 (PITX2) [ 47 ], forkhead box protein O1 (FOXO1) [ 48 ], T-box transcription factor TBX5 [ 49 , 50 ], Runt-related transcription factor 1/2 (RUNX1/2) [ 51 , 52 , 53 , 54 ] and YAP/TAZ competing factors such as vestigial-like family member 4 (VGLL4) [ 55 , 56 , 57 ] ( Figure 1 ). Hippo signaling activity can be regulated by variable upstream factors like kidney and brain expressed protein (KIBRA) [ 58 ], neurofibromin 2 (NF2) [ 58 ], FERM domain-containing protein 6 (FRMD6) [ 59 ], mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) [ 60 ], striatin-interacting phosphatases and kinases (STRIPAK) [ 61 ], serine/threonine-protein kinase 25 (STK25) [ 62 ], P2Y 2 nucleotide receptor (P2Y 2 R) [ 63 ], thousand-and-one amino acid kinases 1/3 (TAOK1/3) [ 64 , 65 , 66 ] and protocadherin Fat4 (FAT4) [ 67 ]. GPCRs (G-protein-coupled receptors) regulate Hippo signaling via GPCRs-G-protein-cytoskeleton axis [ 68 , 69 ] ( Figure 1 ).…”