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The effect of poly I:C or LPS priming on the therapeutic efficacy of mesenchymal stem cells in an adjuvant-induced arthritis rat model

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Abstract

Background

The immunomodulatory properties of mesenchymal stem cells (MSCs) have made them a prospective treatment option for inflammatory and autoimmune disorders. Recent studies have found an association between the immunomodulatory function of MSCs and Toll-like receptors (TLRs). Here, we investigated the effect of priming with lipopolysaccharide (LPS) as TLR4 ligand or polyinosinic:polycytidylic acid (poly I:C) as TLR3 ligand on the immunomodulatory function of adipose-derived MSCs (ADMSCs) in vitro and for the first time in an adjuvant-induced arthritis model (AIA).

Methods

ADMSCs were treated with LPS or poly I:C for 1 h. Splenocyte proliferation in the presence of primed ADMSCs was assessed in vitro using an MTT assay. Next, we investigated the therapeutic effect of primed ADMSCs in vivo. Male Wistar rats were infused with complete Freund’s adjuvant (CFA) to develop arthritis and then intraperitoneally treated with not-primed, poly I:C- or LPS-primed ADMSCs. Clinical signs, histopathological alteration, and serum and spleen cytokine levels were analyzed.

Results

Poly I:C-primed ADMSCs significantly reduced splenocytes proliferation, while ADMSCs primed with LPS increased splenocytes proliferation. Furthermore, poly I:C-primed ADMSCs significantly alleviated the clinical and histopathological severity and the secretion of inflammatory cytokines associated with Th17/Th1 such as IL-17 and IFN-γ. Poly I:C-primed ADMSCs also increased cytokines IL-10 and TGF-β. TNF-α and IL-6 Levels were also markedly diminished in the serum of AIA animals treated with poly I:C-primed ADMSCs. In contrast, priming ADMSCs with LPS significantly reduced the therapeutic effect of ADMSCs in AIA animals.

Conclusion

As a result of these findings, poly I:C priming may be a new technique for improving the therapeutic effects of MSCs in arthritic disorders.

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All data will be available upon request.

Abbreviations

AIA:

Adjuvant-induced arthritis

CFA:

Complete Freund’s adjuvant

DMEM:

Dulbecco’s modified Eagle’s medium

EDTA:

Ethylenediamine tetra-acetic acid

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal Bovine Serum

IDO:

Indoleamine 2 3-dioxygenase

IFN-γ:

Interferon gamma

IL-6:

Interleukin-6

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MTT:

Thiazolyl blue tetrazolium bromide

NF-κB:

Nuclear-factor-kappa B

PBS:

Phosphate-buffered saline solution

PHA:

Phytohemagglutinin

PGE2:

Prostaglandin E2

Poly I:C:

Polyinosinic:polycytidylic acid

TGF-β:

Transforming growth factor beta

Tregs:

Regulatory T cells Th17, T helper 17 cells

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

NSAIDs:

Nonsteroidal anti-inflammatory drugs

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Funding

This project was supported financially by the Iran University of Medical Sciences, Tehran, Iran (Grant no. 97-03-87-32665).

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Authors and Affiliations

  1. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, 1591639675, Iran

    Samira Zolfaghari, Peiman Brouki Milan, Motahareh Rajabi Fomeshi, Fatemeh Eskandari, Loghman Ebrahimi & Mohammad Taghi Joghataei

  2. Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Samira Zolfaghari, Peiman Brouki Milan, Motahareh Rajabi Fomeshi, Fatemeh Eskandari, Loghman Ebrahimi & Mohammad Taghi Joghataei

  3. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Ahmad Reza Dehpour

  4. Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717434, Iran

    Seyed Mahmoud Hashemi

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  1. Samira Zolfaghari
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  2. Peiman Brouki Milan
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  3. Ahmad Reza Dehpour
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  4. Motahareh Rajabi Fomeshi
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  7. Seyed Mahmoud Hashemi
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Contributions

SZ lfaghari designed and performed experiments, analyzed data, and wrote the manuscript; PBM contributed to the development of the protocol and corrected the manuscript; ARD contributed to the final version of the manuscript; MRF contributed to animal studies; FE contributed to cell preparation; SMH verified the analytical data and helped supervise the project; MTJ supervised the project. All the authors read and approved the final manuscript.

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Correspondence to Seyed Mahmoud Hashemi or Mohammad Taghi Joghataei.

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Zolfaghari, S., Milan, P.B., Dehpour, A.R. et al. The effect of poly I:C or LPS priming on the therapeutic efficacy of mesenchymal stem cells in an adjuvant-induced arthritis rat model. Pharmacol. Rep 74, 654–668 (2022). https://doi.org/10.1007/s43440-022-00386-9

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