Cardiomyocyte‐GSK‐3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms

Abstract

Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here, we sought to identify the potential roles of glycogen synthase kinase‐3β (GSK‐3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation post‐myocardial infarction (MI). Cardiomyocyte‐specific conditional GSK‐3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension and contractile functions were comparable at 2 weeks post‐MI, cKO mice displayed significantly preserved LV chamber and contractile function versus control mice at 4 weeks post‐MI. Consistent with protective phenotypes, an increased percentage of c‐kit‐positive cells (KPCs) were observed in the cKO hearts at 4 and 6 weeks post‐MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage, as the majority of identified KPCs were negative for the hematopoietic lineage marker, CD45. Mechanistically, cardiomyocyte‐GSK‐3β profoundly suppresses the expression and secretion of growth factors, including basic‐fibroblast growth factor, angiopoietin‐2, erythropoietin, stem cell factor, platelet‐derived growth factor‐BB, granulocyte colony‐stimulating factor, and vascular endothelial growth factor, post‐hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte‐GSK‐3β promotes cardiomyocyte and resident CPC proliferation post‐MI. The induction of cardiomyocyte and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post‐MI. A strategy to inhibit cardiomyocyte‐GSK‐3β could be helpful for the promotion of in situ cardiac regeneration post‐ischemic injury.

SARS-CoV-2 infection- induced growth factors play differential roles in COVID-19 pathogenesis

“…A flow cytometry-based multiplex assay was performed using a flow cytometry-based LegendPlex kit (BioLegend #740180) to assess the levels of 13 plasma GFs including angpt-2, FGF-basic, TGF-α, EGF, EPO, M-CSF, G-CSF, GM-CSF, SCF, HGF, PDGF-AA, PDGF-BB, and VEGF following manufacturer's instruction as reported previously [4] . Briefly, plasma samples from COVID-19 patients and healthy controls were diluted 1:1 and used to measure the levels of mentioned growth factors.…”

“…GFs are biologically active intermediate molecules secreted by various cell types during health and diseased conditions [2] . They regulate several pathophysiological conditions including tissue injury and repair through binding to specific receptors on the cell via paracrine and/or autocrine mechanisms [3] , [4] . SARS-CoV-2-induced cytokines and GFs mediate coagulation dysfunction and tissue injury, which contribute to the clinical severity of COVID-19 [5] , [6] .…”

WNT/β‐catenin pathway is a key regulator of cardiac function and energetic metabolism

“…31,94 Inducible cardiac-specific GSK3β deletion also improves heart healing after infarction and limits heart dilatation. 182,183 Interestingly, βcatenin deletion is also cardioprotective and reduces susceptibility to arrhythmias after myocardial infarction, likely through the attenuation of structural remodeling. 184 Proper βcatenin cascade activity maintains the resident CPC population in the adult heart.…”

“…β‐catenin activation stimulates prosurvival antiapoptotic gene expression ( Bcl‐2 and survivin ) and provides less reactive oxygen species (ROS)‐producing energy substrate through upregulation of the lactate transporter Slc16a3 31,94 . Inducible cardiac‐specific GSK3β deletion also improves heart healing after infarction and limits heart dilatation 182,183 . Interestingly, β‐catenin deletion is also cardioprotective and reduces susceptibility to arrhythmias after myocardial infarction, likely through the attenuation of structural remodeling 184 …”

Natural compound screening predicts novel GSK-3 isoform-specific inhibitors

“…Glycogen synthase kinase-3 (GSK-3) serves as a critical connection in complex cellular signaling pathways [1]. It is implicated in a diverse range of cellular processes ranging from cell growth and proliferation to cell death and metabolic control [1][2][3][4]. Aberrant activity of GSK-3 leads to dysregulation of cellular processes that underscore a variety of clinical conditions such as diabetes, inflammation, cancer, cardiovascular diseases and neurodegeneration [5].…”