PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact.

Byung-Chul Lee,Jin Young Lee,Kyung-Rok Yu,Kyung-Sun Kang,Insung Kang,Soon Won Choi,Hyung-Sik Kim,Seunghee Lee,Jae-Jun Kim,Hyun Kyoung Kang,Yoojin Seo,Tae-Hoon Shin

doi:10.1038/srep26298

Abstract

Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E2 (PGE2), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE2 on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE2 secretion, and proliferation was assessed. PGE2 exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE2 production led to growth arrest, whereas addition of MSC-derived PGE2 restored proliferation. The level of PGE2 production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE2 secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE2 produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE2 secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency.

Highlights

Mesenchymal stem cells (MSCs) are potential candidates for the treatment of immune disorders such as graft-versus-host disease, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis[1]
We investigated whether selective inhibition of COX-2 using celecoxib or inhibition of membrane associated PGE synthase 1, a Prostaglandin E2 (PGE2) synthesizing enzyme downstream of COX-2 signalling, using cay10526 affected the proliferative phenotype of hUCB-MSCs and hAD-MSCs
We found that PGE2 produced by hUCB-MSCs and hAD-MSCs plays a crucial role in the maintenance of their proliferative function by regulating COX-2 signalling using chemical inhibitors or small interfering RNA (siRNA) for COX-2

Summary

Introduction

MSCs are potential candidates for the treatment of immune disorders such as graft-versus-host disease, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis[1]. Several groups have manipulated the cells by pre-treating MSCs with growth factors and cytokines or by genetic modification[4,5] These approaches are controversial because the precise mechanisms based on selected www.nature.com/scientificreports/. In tumour-progressing cells, EP2 receptor is highly expressed, while the EP3 receptor expression level is relatively low[12,13] This COX-2/PGE2 axis forms an autocrine/paracrine loop, affecting the cell cycle and apoptosis to regulate cell proliferation and viability via the activation of one or more EP receptors[14]. This study was designed to reveal the regulatory mechanism of PGE2 production in adult stem cells by gap junction intercellular communication (GJIC) when intimate cell-to-cell contact is allowed. We generalized the PGE2-mediated novel properties of human adult stem cells using hUCB-MSCs and hAD-MSCs

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Results

Conclusion