All-Trans Retinoic Acid Improves the Effects of Bone Marrow-Derived Mesenchymal Stem Cells on the Treatment of Ankylosing Spondylitis: AnIn VitroStudy

Abstract

Previous studies have demonstrated the immunosuppressive effects of both all-trans retinoic acid (ATRA) and mesenchymal stem cells (MSCs). The present study aimed to assess the immunoregulatory effects of ATRA on MSCs in the treatment of ankylosing spondylitis (AS). Bone marrow-derived MSCs from healthy donors were pretreated with ATRA and cocultured with CD3/28-activated peripheral blood mononuclear cells (PBMCs) derived from AS patients. Frequencies of Th17 and regulatory T (Treg) cells were analyzed using flow cytometry. The secretion and the mRNA level of key cytokines were measured with cytometric bead array and quantitative real-time PCR, respectively. ATRA pretreatment increased interleukin-6 (IL-6) secretion of MSCs. Th17 and Treg subset populations were increased and reduced by ATRA-pretreated MSCs, respectively. ATRA-pretreated MSCs significantly decreased not only the vital pathogenic cytokine in AS, tumor necrosis factor-α (TNF-α), but also AS-boosting factors interleukin-17 (IL-17A) and interferon-γ (IFN-γ). These results indicated that IL-6 may be a potential protective factor in AS and highlighted the promising role of ATRA in improving the efficacy of MSC-based treatment of AS.

Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies

“… [ 101 ] ATRA Bone marrow Ankylosing spondylitis model In vitro Decreased secretion of inflammatory cytokines TNF-α, IL-17A and IFN-γ; increased IL-6 secretion; induced Treg. [ 102 ] Rapamycin (short exposure) Bone marrow – In vitro Upregulated COX-2/PGE2; decreased PBMCs and splenocytes proliferation. [ 99 ] VPA valproic acid, S P1 sphingosine-1-phosphate, 5-aza-dC 5-aza-2′-deoxycytidine, DFO desferrioxamine, DNP 2,4-dinitrophenol, DMOG dimethyloxalylglycine, ISO isoflurane, CCPA 2-chloro-N6-cyclopentyl-adenosine, TGF-β1 transforming growth factor β1, IGF insulin growth factor, ATRA all-trans retinoic acid …”

“…In addition, human BM-MSC primed with ATRA, when cocultured in vitro with activated peripheral blood mononuclear cells from ankylosing spondylitis (AS) patients, secreted high levels of IL-6 and induced the expansion of Treg subsets. Moreover, ATRA-primed MSC modulated the inflammatory cytokine profile of PBMC from AS patients, reducing the secretion of TNF-α, IL-17A, and IFN-γ [ 102 ] (Table 3 ).…”

Role of bone marrow‐derived mesenchymal stem cell defects in CD8+CD28– suppressor T‐lymphocyte induction in patients with immune thrombocytopenia and associated mechanisms

“…Thus, we examined the associated mechanism and found that BM-MSCs reinforced IL-10 secretion. Given the key role of IL-10 in Ts cell suppression, 20 Because ATRA causes MSCs to induce Tregs and increases IL-6 secretion by MSCs, 21 we successfully improved the Ts cell percentage induction ability of ITP BM-MSCs by ATRA preconditioning; however, there was no effect on Ts cell function. As BM-MSC apoptosis, proliferation, and immune regulation are abnormal in patients with ITP, we tried to use UC-MSCs to correct Ts abnormalities in patients with ITP.…”

TNF-αInduced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2

“…Total RNA of MSCs was extracted using TRIzol reagent (Invitrogen, USA) and transcribed into cDNA using PrimeScript™ RT Master Mix (Takara, Japan). qRT-PCR was carried out in triplicate for each sample on a LightCycler® 480 PCR System (Roche, Switzerland) using SYBR® Premix Ex Taq™ (Takara, Japan) as previously described [ 26 ]. GAPDH was used as the housekeeping gene.…”