A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD

Abstract

BackgroundMesenchymal stromal cells (MSCs) are a promising therapy for preventing chronic Graft-Versus-Host Disease (cGVHD) due to their potent immunomodulatory properties. However, the safety concerns regarding the use of MSCs remain unsolved, and conflicting effects are observed due to the heterogeneity of MSCs. Recently, exosomes were shown to mediate the paracrine effects of MSCs, making it a potential candidate for cell-free therapies. The aim of this study is to investigate the efficacy and safety of MSCs-derived exosomes (MSCs-exo) in an established cGVHD mouse model.MethodsBone marrow (BM)-derived MSCs were cultured, and the supernatants of these cultures were collected to prepare exosomes using ultracentrifugation. Exosomes from human dermal fibroblasts (Fib-exo) were used as a negative control. The cGVHD model was established, and tail vein injections of MSCs-exo or Fib-exo were administered once per week for 6 weeks. The symptoms and signs of cGVHD were monitored, and histopathological changes were detected by hematoxylin and eosin and Masson staining. The effects of MSCs-exo on Th17, Th1, and Treg were evaluated by flow cytometry, qPCR, and Luminex. In addition, human peripheral blood mononuclear cells (PBMCs) were stimulated and treated with MSCs-exo in vitro. IL-17-expressing Th17 and IL-10-expressing Treg were evaluated by flow cytometry, qPCR, and ELISA.ResultsWe found that MSCs-exo effectively prolonged the survival of cGVHD mice and diminished the clinical and pathological scores of cGVHD. Fibrosis in the skin, lung, and liver was significantly ameliorated by MSCs-exo application. In MSCs-exo treated mice, activation of CD4+ T cells and their infiltration into the lung were reduced. Of note, MSCs-exo exhibited potent immunomodulatory effects via the inhibition of IL-17-expressing pathogenic T cells and induction of IL-10-expressing regulatory cells during cGVHD. The expressions of Th17 cell-relevant transcription factors and pro-inflammatory cytokines was markedly reduced after MSCs-exo treatment. In vitro, MSCs-exo blocked Th17 differentiation and improved the Treg phenotype in PBMCs obtained from healthy donors and patients with active cGVHD, further indicating the regulatory effect of MSCs-exo on GVHD effector T cells.ConclusionsOur data suggested that MSCs-exo could improve the survival and ameliorate the pathologic damage of cGVHD by suppressing Th17 cells and inducing Treg. This finding provides a novel alternative approach for the treatment of cGVHD.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0680-7) contains supplementary material, which is available to authorized users.

Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm

“…Therapeutic effects of MSC-derived exosomes in liver, kidney, cardiovascular, and neurological diseases functional MHC-peptide complexes to modulate tumor-specific T cell activation [54]. Exosomes released from Bone marrow (BM)-derived MSCs can effectively ameliorate chronic graft-versus-host disease (cGVHD) in mice by inhibiting the activation and infiltration of CD4 T cells, reducing pro-inflammatory cytokine production, as well as improving the generation of IL-10-expressing Treg and inhibiting Th17 cells [55]. Human multipotent stromal cells-derived EVs suppress autoimmunity in models of type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU).…”

“…Improved preclinical study quality in terms of treatment allocation reporting, randomization and blinding will accelerate needed progress towards clinical trials that should assess the feasibility and safety of this therapeutic approach in humans [61]. For example, MSC-exosomes will be great adipose derived-MSCs hepatitis TNF-α, IFN-γ, IL-6, IL-18 and IL-1β [33] human umbilical cord-derived MSCs renal Ischemia-reperfusion injury (IRI) VEGF [34] adipose tissue-derived autologous MSCs renal artery stenosis TNF-α, IL-6, IL10 and IL-1-β [35] human bone marrow MSCs acute kidney injury mRNAs [36] bone marrow MSCs acute renal injury Bcl-xL,Bcl2, BIRC8,Casp1, Casp8 and LTA [37] human umbilical cord MSCs unilateral renal ischemia lipocalin [38] bone marrow MSCs acute kidney injury mRNAs [36] Human bone marrow MSCs damaged renal tubular IGF-1R [39] adipose-derived MSC myocardial ischemia-reperfusion injury Wnt/β-catenin [41] endometrium-derived MSCs myocardial infarction miR-21, PTEN [42] HuES9.E1 derived MSCs myocardial ischemia/reperfusion injury PI3K/Akt [43] mouse bone marrow-derived MSCs myocardial infarction miR-22, Mecp2 [44] bone marrow MSCs myocardial infarction miR-125b [45] human mesenchymal stem cell cardiac contractility miR-21-5p, PI3K [46] bone marrow-derived MSCs myocardial ischaemia reperfusion injury AMPK/mTOR, Akt/mTOR [47] rat bone marrow derived MSCs stroke miR-17-92, PTEN [50] human adipose tissue-derived MSCs Alzheimer's disease neprilysin [51] adipose-derived stem cells oxygen-glucose deprivation MicroRNA-181b/TRPM7 [52] mouse bone marrow MSCs Alzheimer's disease STAT3, NF-κB [ 53] bone marrow derived MSCs chronic graft-versus-host disease Treg, Th17 [55] human multipotent stromal cells type 1 diabetes, uveoretinitis Th1, Th17 [56] human bone-marrow derived MSCs asthma IL-10, TGF-β1 [ 57] human umbilical cord MSCs inflammation MiR-181c, TLR4 [58] biological tools for cancer therapy, it is hopeful to delve deeper into the potential of MSC-exosomes among cancer cells and provide effective treatments with the highest safety [62] Table 2.…”

Stem Cell-Derived Exosomes in Autism Spectrum Disorder

“…The positive effect of exosomes is amply documented in several pathologies: Lai et al in 2018 suggested that MSC-derived exosomes could improve graft versus host disease in mice through the inhibition of CD4 T cells [24]. In addition, the exosomes exhibit immune-modulatory properties by activating the regulatory T cells and blocking Th17 cells; Cui et al in 2018 concluded that adipose-derived MSCs (ADMSCs) exosomes were able to rescue ischemic myocardium from ischemia/reperfusion damage by the action of their anti-apoptotic and pro-survival properties on cardiomyocytic cells.…”

Mesenchymal Stromal Cells’ Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

“…In 2010, the therapeutic potential of MSC-derived EVs was tested in a mouse model of ischemia (Lai et al, 2010 ). Since then, EVs have been investigated in several other disease models, such as cardiovascular disorders (Wang N. et al, 2017 ), kidney injury (Aghajani Nargesi et al, 2017 ; Farzamfar et al, 2019 ), immune diseases (Lai et al, 2018 , 2019 ), tumor growth (Wu et al, 2013 ; Zhang et al, 2017 ) and neurological diseases (Wang et al, 2018 ; Gorabi et al, 2019 ), obtaining encouraging results (Yu et al, 2014 ).…”