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

Carl Randall Harrell, Dragica Miloradovic, Ruxana Sadikot, Crissy Fellabaum, Bojana Simovic Markovic, Dragana Miloradovic, Aleksandar Acovic, Valentin Djonov, Nebojsa Arsenijevic, Vladislav Volarevic

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Article number3153891
JournalAnalytical Cellular Pathology
Volume2020
DOIs
StatePublished - 2020
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Medicine
  • Cell Biology
  • Cancer Research

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