Polo‐Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes‐Associated Protein 1 in Cardiac Progenitor Cells

Abstract

BackgroundRecent studies suggest that adult cardiac progenitor cells (CPCs) can produce new cardiac cells. Such cell formation requires an intricate coordination of progenitor cell proliferation and commitment, but the molecular cues responsible for this regulation in CPCs are ill defined.Methods and ResultsExtracellular matrix components are important instructors of cell fate. Using laminin and fibronectin, we induced two slightly distinct CPC phenotypes differing in proliferation rate and commitment status and analyzed the early transcriptomic response to CPC adhesion (<2 hours). Ninety‐four genes were differentially regulated on laminin versus fibronectin, consisting of mostly downregulated genes that were enriched for Yes‐associated protein (YAP) conserved signature and TEA domain family member 1 (TEAD1)‐related genes. This early gene regulation was preceded by the rapid cytosolic sequestration and degradation of YAP on laminin. Among the most strongly regulated genes was polo‐like kinase 2 (Plk2). Plk2 expression depended on YAP stability and was enhanced in CPCs transfected with a nuclear‐targeted mutant YAP. Phenotypically, the early downregulation of Plk2 on laminin was succeeded by lower cell proliferation, enhanced lineage gene expression (24 hours), and facilitated differentiation (3 weeks) compared with fibronectin. Finally, overexpression of Plk2 enhanced CPC proliferation and knockdown of Plk2 induced the expression of lineage genes.ConclusionsPlk2 acts as coordinator of cell proliferation and early lineage commitment in CPCs. The rapid downregulation of Plk2 on YAP inactivation marks a switch towards enhanced commitment and facilitated differentiation. These findings link early gene regulation to cell fate and provide novel insights into how CPC proliferation and differentiation are orchestrated.

Hypoxia-induced epigenetic silencing of polo-like kinase 2 promotes fibrosis in atrial fibrillation

“…We demonstrate that PLK2 inhibition or KO induce myofibroblast differentiation and consequently reduce cell proliferation in cardiac fibroblasts. This finding fits well to a recent study showing PLK2 as a key regulator for proliferation and differentiation in cardiac progenitor cells (Mochizuki et al, 2017). Moreover, primary human cardiac fibroblasts from AF patients were shown to differentiate into myofibroblasts to a greater extent and to proliferate less compared to SR controls (Poulet et al, 2016).…”

“…An Affymetrix ® microarray (Poulet et al, 2016) revealed negative regulation of polo-like kinase 2 (PLK2) transcripts. PLK2 is a serinethreonine kinase that regulates cell cycle progression by centriole duplication and it is strongly associated with cell proliferation, mitochondrial respiration and apoptosis (Mochizuki et al, 2017;Li et al, 2014;Ma et al, 2003, 2). Published data suggest that PLK2 suppression may induce cellular senescence (Deng et al, 2017), a condition in which cells stop to proliferate (Coppé et al, 2008).…”

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

“…Utilizing a cardiac organoid model, Mills et al (2017) showed that YAP deactivation is associated with a switch to fatty acid metabolism that in turn inhibits proliferation and promotes cardiomyocyte maturation. Mochizuki et al (2017) reported that YAP deactivation leads to downregulation of polo-like kinase 2, which in turn enables cardiac progenitors to switch from the proliferative to the terminal differentiation phase.…”

“…The role of YAP/TAZ in cardiomyogenesis was first revealed by studies on fetal heart development. Fetal cardiomyocytes undergo extensive proliferation that ends abruptly after birth, and these changes are strongly correlated with YAP activation and deactivation, respectively ( Del Re et al, 2013 ; Xin et al, 2013 ; Lin et al, 2014 , 2015 ; Mosqueira et al, 2014 ; Cho et al, 2017 ; Estarás et al, 2017 ; Hou et al, 2017 ; Khalafalla et al, 2017 ; Mills et al, 2017 ; Mochizuki et al, 2017 ; Ragni et al, 2017 ; Artap et al, 2018 ; Wang X. et al, 2018 ; Ito et al, 2019 ; Torrini et al, 2019 ). Postnatal heart tissue growth is driven primarily by cardiomyocyte hypertrophy (increase in cell size and deposition of extracellular matrix), rather than increase in cell number ( von Gise et al, 2012 ; Xin et al, 2013 ; Artap et al, 2018 ).…”

Genetic Deletion of Polo-Like Kinase 2 Induces a Pro-Fibrotic Pulmonary Phenotype

“…Polo-like kinase 2 (PLK2) is a serine-threonine kinase that regulates cell cycle progression, cell proliferation, mitochondrial respiration and apoptosis [ 9 , 10 , 11 , 12 ]. There is first evidence that PLK2 regulates fibrosis formation in cardiovascular disease [ 13 ] and differential regulation of PLK2 gene expression was found in Transforming Growth Factor beta 1 (TGF-β) treated adult lung fibroblasts [ 14 ].…”