Old Friends with Unexploited Perspectives: Current Advances in Mesenchymal Stem Cell-Based Therapies in Asthma

Abstract

Mesenchymal stem cells (MSCs) have a great regenerative and immunomodulatory potential that was successfully tested in numerous pre-clinical and clinical studies of various degenerative, hematological and inflammatory disorders. Over the last few decades, substantial immunoregulatory effects of MSC treatment were widely observed in different experimental models of asthma. Therefore, it is tempting to speculate that stem cell-based treatment could become an attractive means to better suppress asthmatic airway inflammation, especially in subjects resistant to currently available anti-inflammatory therapies. In this review, we discuss mechanisms accounting for potent immunosuppressive properties of MSCs and the rationale for their use in asthma. We describe in detail an intriguing interplay between MSCs and other crucial players in the immune system as well as lung microenvironment. Finally, we reveal the potential of MSCs in maintaining airway epithelial integrity and alleviating lung remodeling.

Keywords: Asthma; Experimental asthma; Immune regulation; Mesenchymal stem cells; Stem cells.

Fig. 1

The direct and indirect immunomodulatory mechanism of mesenchymal stem cells. Mesenchymal stem cells exert the immunosuppressive effects by direct (cell-to-cell dependent; marked on the orange background) and indirect (secretome-mediated; marked on the blue background) interactions with immune cells. Induction of immunosuppressive properties of MSCs requires proinflammatory signaling mediated by IL-1α/β, TNF-α, IFNγ, among others. Breg- B regulatory cell; DC- dendritic cell; EVs- extracellular vesicles; FOXO3- forkhead box O3; HGF- hepatocyte growth factor; HO-1-heme oxygenase 1; ICAM- intracellular adhesion molecule 1; ICOS- inducible costimulator; ICOSL- idnucible costimulator ligand; IDO-indoleamine 2,3-dioxygenase; IFNγ- interferon gamma; IL-(1α, 1β, 2, 6, 10, 12, 25, 35)- interleukin 1α, 1β, 2, 6, 10, 12, 25, 35; IL-25R- interleukin 25 receptor; JNK- c-Jun N-terminal kinase; KYN-kynurenine; LFA-1- lymphocyte function-associated antigen 1; MSC-mesenchymal stem cell; PD-1- programmed cell death receptor 1; PD-L(1/2)- programmed death-ligand 1/2; PGE2- prostaglandin E2; PI3K/ AKT- phosphoinositide 3-kinase/ protein kinase B; STAT3- signal transducer and activator of transcription 3; TGFβ- transforming growth factor β; TNF-α- tumor necrosis factor α; Treg- T regulatory cell; TRP- tryptophan; VCAM1- vascular cell adhesion protein 1; VLA4- very late antigen 4, ←activation/ induction; ├ inhibition; ↑increase; ↓decrease

Fig. 2

Mesenchymal stem cells-mediated immunomodulatory effects in the airways. Summary of immunomodulatory effects of mesenchymal stem cells in asthmatic lung inflammation. The set of proinflammatory cytokines secreted in the course of asthma causes the priming of mesenchymal stem cells and induces their immunosuppressive activities. Importantly, induction of regulatory T cells, alternatively activated macrophages (M2), and tolerogenic dendritic cells (DCs) represent to date best-described mechanisms regulating Th2-driven and non-Th2-driven immune responses. CCL(17/22)- chemokine C-C motif ligand 17/22; CCR6- C-C chemokine receptor 6; Cldn(4/18)- claudin 4/18; MSC- mesenchymal stem cell; ZO-1- zonula occludens 1; DC- dendritic cells; EP(2/4)- prostaglandin E2 receptor 2/4; FOXP3- forkhead box p3; IL-(4, 5, 10, 12, 13, 35)- interleukin 4, 5, 10, 12, 13, 35; iNOS- inducible nitric oxide synthase; NO- nitric oxide, PGE2- prostaglandin E2; RORC- RAR-related orphan receptor gamma; TGFβ- transforming growth factor β, ←activation/ induction; ├ inhibition; ← - unknown effect; ↑increase; ↓decrease