Molecular and Cellular Mechanisms Responsible for Beneficial Effects of Mesenchymal Stem Cell-Derived Product “Exo-d-MAPPS” in Attenuation of Chronic Airway Inflammation

Abstract

Mesenchymal stem cells (MSCs), due to their potential for differentiation into alveolar epithelial cells and their immunosuppressive characteristics, are considered a new therapeutic agent in cell-based therapy of inflammatory lung disorders, including chronic obstructive pulmonary disease (COPD). Since most of the MSC-mediated beneficent effects were the consequence of their paracrine action, herewith, we investigated the effects of a newly designed MSC-derived product “Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)” in the attenuation of chronic airway inflammation by using an animal model of COPD (induced by chronic exposure to cigarette smoke (CS)) and clinical data obtained from Exo-d-MAPPS-treated COPD patients. Exo-d-MAPPS contains a high concentration of immunomodulatory factors which are capable of attenuating chronic airway inflammation, including soluble TNF receptors I and II, IL-1 receptor antagonist, and soluble receptor for advanced glycation end products. Accordingly, Exo-d-MAPPS significantly improved respiratory function, downregulated serum levels of inflammatory cytokines (TNF-α, IL-1β, IL-12, and IFN-γ), increased serum concentration of immunosuppressive IL-10, and attenuated chronic airway inflammation in CS-exposed mice. The cellular makeup of the lungs revealed that Exo-d-MAPPS treatment attenuated the production of inflammatory cytokines in lung-infiltrated macrophages, neutrophils, and natural killer and natural killer T cells and alleviated the antigen-presenting properties of lung-infiltrated macrophages and dendritic cells (DCs). Additionally, Exo-d-MAPPS promoted the expansion of immunosuppressive IL-10-producing alternatively activated macrophages, regulatory DCs, and CD4+FoxP3+T regulatory cells in inflamed lungs which resulted in the attenuation of chronic airway inflammation. In a similar manner, as it was observed in an animal model, Exo-d-MAPPS treatment significantly improved the pulmonary status and quality of life of COPD patients. Importantly, Exo-d-MAPPS was well tolerated since none of the 30 COPD patients reported any adverse effects after Exo-d-MAPPS administration. In summing up, we believe that Exo-d-MAPPS could be considered a potentially new therapeutic agent in the treatment of chronic inflammatory lung diseases whose efficacy should be further explored in large clinical trials.

Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of SARS-CoV-2-Induced Acute Respiratory Distress Syndrome

“…MSC-EVs contain MSC-derived bioactive molecules (microRNAs (miRNAs), enzymes, cytokines, chemokines, and immunomodulatory and growth factors) that generate a tolerogenic phenotype in lung-infiltrated DCs and macrophages which results in enhanced expansion of immunosuppressive Tregs in injured lungs and leads to the alleviation of ongoing inflammation [ 18 , 33 ]. As recently demonstrated by us and others [ 34 , 35 ], in a similar manner as their parental cells, MSC-EVs efficiently attenuated detrimental immune responses in the lungs and promoted enhanced lung repair and regeneration. Reduced expression of costimulatory molecules, downregulated production of Th1- (IL-12, TNF- α , and IFN- γ ) and Th17-inducing cytokines (IL-1, IL-6, and IL-23), and attenuated capacity of antigen-presentation capacity were noticed in DCs and macrophages isolated from the inflamed lungs of MSC-EV-treated animals [ 34 , 35 ].…”

“…Reduced expression of costimulatory molecules, downregulated production of Th1- (IL-12, TNF- α , and IFN- γ ) and Th17-inducing cytokines (IL-1, IL-6, and IL-23), and attenuated capacity of antigen-presentation capacity were noticed in DCs and macrophages isolated from the inflamed lungs of MSC-EV-treated animals [ 34 , 35 ]. Consequently, significantly lower number of lung-infiltrating, inflammatory, TNF- α - and IFN- γ -producing Th1 cells and IL-17-producing Th17 cells and significantly higher number of immunosuppressive, IL-10- and TGF- β -secreting Tregs were found in MSC-EV-treated mice [ 34 , 35 ].…”

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

“…Moreover, the exosomes are capable of affecting the migratory and antigen-presenting properties of DCs, which contribute to the attenuated activation of CD4+ and CD8+ T lymphocytes. Importantly, this study has also demonstrated that inhalation of MSC-exosomes indicate an improved FEV1, PEF, 6-min walking distance (6MWD) and quality of life in COPD patients, with alleviated emphysematous changes, including less hyperexpanded lung, less flattened diaphragms and reduced centrilobular and paraseptal emphysema [94]. In what could be another mechanism for MSC-EVs in COPD, Kim et al have shown that unlike MSC-derived natural exosomes, MSC-derived artificial nanovesicles (3 × 10 7 artificial nanovesicle particles generated from 7 × 10 7 ASCs) display a more efficient regenerative capacity to reduce the mean linear intercept (MLI) primarily through activating the FGF-2 signalling pathway [95].…”

Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: Mechanisms of action, research progress, challenges, and opportunities

“…As the lungs are in direct contact with the external environment, they are prone to different infections including viral diseases. Over the past decade, a considerable number of studies shed light on the therapeutic effects of MSCs for lung diseases, such as ARDS [19] , [20] , [21] , [22] , [23] , chronic obstructive pulmonary disease (COPD) [24] , [25] , [26] , [27] , [28] , Asthma [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , and idiopathic pulmonary fibrosis (IPF) [43] , [44] , [45] , [46] , [47] , [48] .…”