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

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.

Growth Factor-free Chondrogenic Differentiation from Induced Pluripotent Stem Cells using Minicircle Vectors

“…Safe and efficient gene transfer is promising for the use of gene-modified stem cells in therapeutic applications [25]. The effect of minicircle vectors encoding human proteins was confirmed through our preliminary researches [26][27][28]. The combination of minicircle vectors and stem cells can suggest a new regenerative tool for clinical application.…”

“…Even with minicircles, we previously reported low transfection in bone marrow-derived MSCs using chemical transfection reagents [26]. The transfection efficacy in MSCs was increased when using electroporation along with minicircle vectors.…”

A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

“…The minicircles (mcMock and mcTNFR2) were kindly donated by Dr. Ji Hyeon J in the Catholic University of Korea [11]. Briefly, ZYCY10P3S2T competent cells transformed with the parental plasmids were grown overnight at 37 • C in Terrific Broth containing 50 µg/mL kanamycin.…”

“…Etanercept has been approved by the US FDA for the treatment of a number of autoimmune diseases, including rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis [10]. Etanercept is a fusion protein that is formed due to the binding between the p75 region of TNF receptor 2 and the Fc portion of immunoglobulin ( Figure 1A) [10][11][12]. Although having higher therapeutic potential, etanercept can be categorized as an expensive medicine because it is produced through a series of recombination and purification processes.…”

Exploring the Role of Mesenchymal Stem Cells During Normothermic Organ Perfusion: A New Paradigm to Enhance Outcome Following Allograft Transplantation

“…This was explained by various reasons including the in vitro microenvironment, type and donor age, Isolation techniques and site of isolation [27]. A surge of trials is underway tackling these challenges including proposals [27] utilising genetic modifications and targeted delivery systems with P-Selectin Glycoprotien Ligand-1 [28] or Etanercept [29]. We propose a novel technique in using MSC during ex-vivo normothermic kidney perfusion utilising the plasticity of MSC in organ optimisation and minimising the effect of reperfusion injury through their anti-apoptotic and anti-inflammatory functions.…”