A Prokineticin‐Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate. (31st July 2018)

• Record Type: Journal Article
• Authors: Qureshi, Rehana; Kindo, Michel; Boulberdaa, Mounia; von Hunolstein, Jean‐Jacques; Steenman, Marja; Nebigil, Canan G.
• Is Part Of: Stem cells. Volume 36:Number 10(2018)
• Page Start: 1589
• Page End: 1602
• Publication Date: 2018-07-31
• Subjects: Epicardial‐derived progenitor cells -- Prokineticin -- KDM6A/UTX -- H3K27me3 -- Epicardial adipose tissue -- Self‐renewal -- Asymmetric division -- Differentiation -- Epicardial to mesenchymal transformation -- Angiogenesis -- Vascular smooth muscle cells; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2866
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Epicardial adipose tissues (EATs) and vascular tissues may both belong to the mesoepithelial lineage that develops from epicardium‐derived progenitor cells (EPDCs) in developing and injured hearts. Very little is known of the molecular mechanisms of EPDC contribution in EAT development and neovascularization in adult heart, which the topic remains a subject of intense therapeutic interest and scientific debate. Here we studied the epigenetic control of stemness and anti‐adipogenic and pro‐vasculogenic fate of human EPDCs (hEPDCs), through investigating an angiogenic hormone, prokineticin‐2 (PK2) signaling via its receptor PKR1. We found that hEPDCs spontaneously undergoes epithelial‐to‐mesenchymal transformation (EMT), and are not predestined for the vascular lineages. However, PK2 via a histone demethylase KDM6A inhibits EMT, and induces asymmetric division, leading to self‐renewal and formation of vascular and epithelial/endothelial precursors with angiogenic potential capable of differentiating into vascular smooth muscle and endothelial cells. PK2 upregulates and activates KDM6A to inhibit repressive histone H3K27me3 marks on promoters of vascular genes ( Flk‐1 and SM22α) involved in vascular lineage commitment and maturation. In PK2‐mediated anti‐adipogenic signaling, KDM6A stabilizes and increases cytoplasmic β‐catenin levels to repress peroxisome proliferator‐activated receptor‐γ expression and activity. Our findings offer additional molecular targets to manipulate hEPDCs‐involved tissue repair/regeneration in cardiometabolic and ischemic heart diseases.Stem Cells 2018;36:1589–1602 Abstract : Epigenetic control of stemness and differentiation of epicardial progenitor cells via an angiogenic hormone prokineticin‐2 (PK2). Here we showed PK2 signaling activates KDM6A that orchestrates stemness and differentiation of human epicardium‐derived progenitor cells (hEPDCs) into vasculogenic and adipogenic cells. PK2 via histone modifications by a demethylase (KDM6A) signaling inhibits epithelial‐to‐mesenchymal transformation and induces asymmetric division of hEPDCs to balance the proliferation and differentiation, thereby keeping the hEPDC in epithelial stage and their numbers constant. PK2 upregulates and activates KDM6A to inhibit repressive histone H3K27me3 marks on promoters of vascular genes involved in endothelial cells and smooth muscle cell lineage commitment. PK2 via KDM6A stabilizes and increases cytoplasmic β‐catenin levels to repress peroxisome proliferator‐activated receptor‐γ expression and activity to inhibit adipogenesis in the context of adipogenic stimuli.