Immunomodulatory benefits of mesenchymal stem cells treated with Caffeine in adjuvant-induced arthritis

Highlights

• Mesenchymal stem cells (MSCs) have the potential to reduce the severity of rheumatoid arthritis (RA).

• Caffeine at 0.5 mM concentration led to an enhancement in the immunomodulatory benefits of MSCs.

• Treatment of RA rats with Caffeine pulsed MSCs led to better outcomes compared to the treatment with un-pulsed MSCs.

Abstract

Purpose

We intend to assess the effect of the conditioned medium of Caffeine pulsed MSCS in the amelioration of rheumatoid arthritis (RA)-afflicted rats.

Methods

MSCs were incubated with 0, 0.1, 0.5 or 1 mM Caffeine for 2 weeks. RA was induced by the injection of complete Freund's adjuvant (CFA) into the base of the tail of Wistar rats. According to in vitro studies, RA rats were intraperitoneally treated with MSCs, Caffeine (0.5 mM) pulsed MSCs or vehicle on day 14 when all rats had shown signs of RA.

Results

Our results suggest that the least effective dose concentration of Caffeine that can induce potent anti-inflammatory property in the MSC population is 0.5 mM. Without any significant impact on the vitality or MScs' marker, Caffeine at this concentration could induce lower levels of IFN-γ, IL-6, and IL-1β and a higher level of IDO, TGF-β, and IL-10 compared to other groups. Therefore, MSCs pulsed with Caffeine at 0.5 mM concentration was selected for in vitro studies. Caffeine pulsed MSCs could reduce the severity of the disease and improve weight-gaining more profoundly than treatment with MSCs alone. Furthermore, Caffeine pulsed MSCs caused a significant reduction in the serum levels C-reactive protein, Nitric oxide, Myeloperoxidase, TNF-α and conversely led a significant increase in the levels of IL-10 more prominent than the similar findings brought about by MSCs alone.

Conclusion

In general, caffeine-treated MSCs may be a promising strategy for cell-based therapy of RA.

Introduction

Mesenchymal stem cells (MSCs) are one of the major groups of stem cells, which have self-renewal multipotent progenitor cells with the capacity to produce several mesenchymal lineages (e.g., Bone, fat, and cartilage) [1]. They are usually found in the bone marrow, peri-endothelial region, and dermal tissue [2]. According to the previous studies, MSCs possess potent immunoregulatory properties that can be a method to control and treat the autoimmune disease [3,4].

Caffeine (1, 3, and 7- trimethylxanthine) is a well- known xanthine alkaloid mostly found in coffee, chocolate, kola nuts, and soft drinks, which affects endocrine, cardiovascular, respiratory, urinary, nervous, gastrointestinal metabolism, and more importantly, the immune system. Caffeine is the most widely consumed beverage with medicinal effects [[4], [5], [6]]. Notably, the structure of Caffeine is very similar to adenosine, which connects to adenosine receptors and acts as a competitive antagonist of adenosine. Adenosine signaling is one of the most various receptors in a wide range of organisms [3,6]. Interestingly, MSCs express adenosine receptors and secrete adenosine, which can regulate the proliferation and differentiation of these cells through autocrine or paracrine routs. Caffeine can also inhibit phosphodiesterase (e.g., PDE1, PDE4, and PDE5) and lead to the calcium release from intracellular poles [5]. According to the previous studies, Tadalafil, a long-acting phosphodiesterase inhibitor, prolonged the MSCs survival due to the down-regulation of Fas, and more importantly, increased MSCs homing into the injured myocardium causing a significant improvement in the infected cardiac function and repair [7]. Therefore, Caffeine can alter the crosstalk between mesenchymal stem cells and their associated cells like immunocytes. More importantly, prior studies indicated that caffeine- treated MSCs could induce an anti-inflammatory phenotype in innate cells of the immunity system. For example, LPS-primed MSCs could reduce the respiratory burst of co-cultured neutrophils. Caffeine treatment of LPS-primed MSCs could reverse this reduction [4].

Rheumatoid Arthritis (RA) is a chronic autoimmune disease with chronic inflammation, lymphocyte infiltration, and destruction of cartilage and bone [8,9]. The local immunopathology is hallmarked by the aggregation of Th1 and Th17 lymphocytes, plasma cells, macrophages and other inflammatory cells, and the expansion of resident stromal and vascular cells [10]. Despite the valuable developments in the control of RA, no medication is curative, nor is the clinical remission presently related to the non-progression of joint destruction. Patients with severe RA may respond to autologous hematopoietic stem cell transplantation. Unfortunately, this therapy shows high morbidity and even a 5% mortality [11]. Because of the regenerative and immunomodulatory properties of MSCs, these cells are the best candidates for cell-based therapy of RA. Nevertheless, some factors (like a decrease in the vitality of MSCs reaching the inflamed area) have restricted their potential therapeutic effects [12]. The present investigation aimed to assess the effect of the conditioned medium of Caffeine pulsed MSCS in amelioration of the rats with rheumatoid arthritis.