Etanercept-Synthesising Mesenchymal Stem Cells Efficiently Ameliorate Collagen-Induced Arthritis

Narae Park,Youngkyun Kim,Seung-Ki Kwok,Hyerin Jung,Ji Hyeon Ju,Sung-Hwan Park,Seung Min Jung,Hyoju Yi,Yeonsue Jang,Yeri Alice Rim,Juryun Kim,Jennifer Lee

doi:10.1038/srep39593

Abstract

Mesenchymal stem cells (MSCs) have multiple properties including anti-inflammatory and immunomodulatory effects in various disease models and clinical treatments. These beneficial effects, however, are sometimes inconsistent and unpredictable. For wider and proper application, scientists sought to improve MSC functions by engineering. We aimed to invent a novel method to produce synthetic biological drugs from engineered MSCs. We investigated the anti-arthritic effect of engineered MSCs in a collagen-induced arthritis (CIA) model. Biologics such as etanercept are the most successful drugs used in anti-cytokine therapy. Biologics are made of protein components, and thus can be theoretically produced from cells including MSCs. MSCs were transfected with recombinant minicircles encoding etanercept (trade name, Enbrel), which is a tumour necrosis factor α blocker currently used to treat rheumatoid arthritis. We confirmed minicircle expression in MSCs in vitro based on GFP. Etanercept production was verified from the conditioned media. We confirmed that self-reproduced etanercept was biologically active in vitro. Arthritis subsided more efficiently in CIA mice injected with mcTNFR2MSCs than in those injected with conventional MSCs or etanercept only. Although this novel strategy is in a very early conceptual stage, it seems to represent a potential alternative method for the delivery of biologics and engineering MSCs.

Highlights

Mesenchymal stem cells (MSCs) are adult stem cells that have immunosuppressive effects against various autoimmune diseases including RA16–18
The generated mcTNFR2 vector was transfected into MSCs to generate mcTNFR2MSCs. mcTNFR2MSCs were delivered to collagen-induced arthritis (CIA) mouse model by intraperitoneal injections to investigate the therapeutic effects on RA
We examined if the transfected mcTNFR2MSCs could synthesise the protein drug in vitro (Fig. 2c). sTNFR2-Fc was highly detected in the culture supernatant of mcTNFR2MSCs; it was not detected in the culture supernatant of non-transfected MSCs or mcMockMSCs

Summary

Introduction

Mesenchymal stem cells (MSCs) are adult stem cells that have immunosuppressive effects against various autoimmune diseases including RA16–18. Scientists are attempting to engineer MSCs in order to improve their function in various ways. It was reported that MSCs engineered with specific genes show improved curative effects[26,27,28]. It remains difficult to transfer a foreign gene into MSCs24. Viruses are the main means by which genes are transferred into MSCs. the use of viruses can induce the integration of foreign genes, which is another hurdle for clinical applications. An improved method to deliver a foreign gene into MSCs is required. Efficacy and safety are the main issues that need to be resolved for MSC engineering by gene transfer for clinical applications. We attempted to generate engineered MSCs named mcTNFR2MSCs using a novel strategy. We hope that the generation of mcTNFR2MSCs using minicircle vectors can make MSC-based treatment more applicable in the future

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