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

• Type of Material: Article
• Authors: Carl Randall Harrell, Regenerative Processing Plant LLC; Dragica Miloradovic, University of Kragujevac; Ruxana Sadikot, Emory University; Crissy Fellabaum, Regenerative Processing Plant LLC; Bojana Simovic Markovic, University of Kragujevac; Dragana Miloradovic, University of Kragujevac; Aleksander Acovic, University of Kragujevac; Valentin Djonov, University of Bern; Nebojsa Arsenijevic, University of Kragujevac; Vladislav Volarevic, University of Kragujevac
• Language: English
• Date: 2020-03-20
• Publisher: Hindawi Ltd.
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Carl Randall Harrell et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1155/2020/3153891
• Title of Journal or Parent Work: Analytical Cellular Pathology
• Volume: 2020
• Start Page: 3153891
• End Page: 3153891
• Grant/Funding Information: This work was supported by the Serbian Ministry of Science (ON175069, ON175103) and the Faculty of Medical Sciences University of Kragujevac (MP01/18).
• Keywords: Cell Biology; COPD; Life Sciences & Biomedicine; Obstructive pulmonary disease; Science & Technology; Receptor; Pathology; Therapy; Oncology; Transplantation; Placenta; Model; Dendritic cells; Stromal cells; Immune responses
• Research Categories: Biology, Molecular; Biology, Cell; Health Sciences, Rehabilitation and Therapy; Health Sciences, Oncology

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-, 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.